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Haematolymphoid Tumours (WHO Classification, 5th ed.)

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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) with BCR-ABL1.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Xinxiu Xu PhD, PharmB, Vanderbilt University Medical Center

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Acute myeloid leukaemia
Type	Acute myeloid leukaemia with defining genetic abnormalities
Subtype(s)	Acute myeloid leukaemia with BCR::ABL1 fusion

Related Terminology


Acceptable	Acute myeloid leukaemia with t(9;22)(q34;q11.2)
Not Recommended	N/A

Gene Rearrangements

The t(9:22)(q34.1;q11.2) results in the formation of the Ph chromosome and the chimeric BCR-ABL1 fusion gene. In AML, ~70 - 80% cases with BCR::ABL1 harbor p210 transcripts, and 50-60% cases with additional chromosomal abnormalities^[1]^[2]^[3]^[4]. The most common BCR-ABL1 transcripts p190 and p210 have been detected in nearly equal distribution^[5]. Since p190 is very rare in CML (p210 transcripts in >99% of cases), the presentation with a p190 transcript is in favor of the diagnosis of AML rather than CML^[6].

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
ABL1	BCR::ABL1	The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	t(9;22)(q34;q11.2)	Common (CML); Rare (AML).	Diagnosis: BCR-ABL1 positive AML is an emerging entity. The proliferation of BCR-ABL1 positive blasts present a diagnostic dilemma. While it may be difficult, it is essential to distinguish between BCR-ABL1 positive AML and Chronic Myeloid Leukemia in Myeloid Blast Crisis (CML-MBC), in order to choose the most appropriate therapy (e.g., intensive induction chemotherapy versus tyrosine kinase inhibitor (TKI) followed by an early allogeneic stem cell transplant). After the exclusion of acute leukemia of ambiguous lineage (a separate entity according to WHO) by flow cytometry, it is helpful to note any past history of antecedent hematological disease. Compared to CML-MBC, a higher percentage of blasts (median: 47% vs 13%), a lower percentage of basophils (median: 0% vs 2.5%) and absolute basophil count, a lower frequency of splenomegaly (25% vs 65%), lower cellularity, fewer dwarf megakaryocytes, and normal M:E ratio favor the diagnosis of BCR-ABL1 positive AML^[2]^[1]. The detection of p190 transcript and the occurrence of any BCR-ABL1 transcript in less than 100% of metaphases supports the diagnosis of AML rather than CML. Persistent CCyR (Complete Cytogenetic Response) after conventional chemotherapy is unusual for CML-MBC and supports the diagnosis of BCR-ABL1 positive AML^[5]. Karyotype analysis that identifies the t(9;22)(q34;q11.2) translocation, either alone or in conjunction with additional chromosomal abnormalities, characterizes BCR-ABL1 positive AML^[1]^[2]. In addition, molecular methods including dual-colour dual-fusion FISH, RT-PCR, qPCR, and RNA or DNA sequencing are used to identify all common breakpoint variants when applicable. Prognosis: The overall prognosis of BCR-ABL1 positive AML is poor, with a median survival time of <9 months^[7]^[1]. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for AML categorize this entity into the poor-risk group, comparable with complex aberrant karyotype AML^[8]. It appears that the prognosis of BCR-ABL1 positive AML depends more on the genetic background (concurrent aberrations) than on BCR-ABL1 itself. Unlike in CML, BCR-ABL1 does not appear to be the key driver in AML though may provide a proliferative advantage to a particular BCR-ABL1 positive subclone. Therapeutics: There is currently no standardized treatment approach for BCR-ABL1 positive AML. Therapy with TKI alone does not produce sustained responses in BCR-ABL1 positive AML^[1]. This may be due to a very rapid clonal evolution, resulting in resistance in a much higher proportion of patients and in a significantly shorter time than in CML^[5].Venetoclax and TKI combination regimens have shown good response in some studies^[9].	Yes (WHO, NCCN)	The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context^[10]^[11]. The prevalence of BCR"" ABL1 in CML is common ~90-95%^[12]. This fusion is responsive to targeted therapy such as Imatinib (Gleevec)^[13]. BCR::ABL1 is generally favorable in CML^[14]^[15]. Three BCR-ABL chimeric proteins result from varying mRNA fusions of the ABL and BCR genes. The most common breakpoint occurs in BCR intron 13 or 14, fusing to ABL1 exon a2 (e13a2, e14a2), yielding a 210 kilodalton protein (p210 BCR-ABL1) found in 95% of CML cases. A rare alternative (<1%) is the e19a2 fusion, producing a 230 kilodalton protein (p230 BCR-ABL1), a marker for neutrophilic-chronic myeloid leukemia. The e1a2 fusion results in the p190 BCR-ABL1 protein, prevalent in B cell ALL, less common in AML, and rare in CML^[16]. The prevalence of BCR::ABL1 in AML is rare (~0.5 - 3%)^[16], per 5th WHO guideline the prevalence is <0.5%^[17]. There is a single case report of an AML patient with BCR::ABL1 achieving molecular remission with dasatinib and chemotherapy^[18]. Outcome of patients < 50 years of age with TKI pretreated BCR::ABL1 positive AML receiving allogeneic stem cell transplant is relatively favorable^[19]. Survival status postallogeneic transplantation appears similar to intermediate risk AML, with one report demonstrating 3 year overall survival of 73%^[20].

Individual Region Genomic Gain/Loss/LOH

AML with BCR-ABL1 carries unique genome imbalances. Nacheva et al., used array comparative genomic hybridization (CGH) to perform a comparative study between several BCR-ABL1 positive entities. BCR-ABL1 positive AML displays characteristic of lymphoid disease (found in BCR-ABL1 positive ALL and CML): deletions of IKZF1 and/or CDKN2A/B genes were recurrent findings in BCR-ABL1 positive AML as well as cryptic deletions within the immunoglobulin IGH and T cell receptor gene (TRG alpha) complexes^[21]. Importantly, these aberrations were found to be absent in CML-MBC and hence they are potentially a helpful diagnostic tool for difficult cases.

Most cases will have monosomy 7/Del(7q), trisomy 8 or complex karyotypes in addition to the t(9;22)(q34.1;q11.2)^[22].

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
7	Loss	chr7	IKZF1, TR Beta Chain (TRB) genes	D,P	No	Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML^[8].
8	Gain	chr8	Unknown	D,P	No	Common recurrent secondary finding for t(8;21)^[23]^[24].

Characteristic Chromosomal or Other Global Mutational Patterns

Additional chromosomal aberrations are infrequently seen in BCR-ABL AML, it has been described together with different class II aberrations such as CBFB-MYH11, RUNX1- RUNX1T1 and PML-RARA^[25]^[5]. In AML, BCR-ABL1 seems to cooperate with several AML-specific aberrations such as inv(16), t(8;21) and myelodysplasia-related cytogenetic aberrations^[5]^[25]. (For diagnostic purpose, note that inv(16) is not restricted to AML and can also be found in CML-MBC). Additional chromosomal aberrations, such as an additional Ph chromosome, trisomy 19 and isochromosome 17q seen in CML MBP are infrequently seen in AML with BCR::ABL1.

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
inv(16)(p13.1q22) or t(16;16)(p13.1;q22)	CBFB::MYH11 fusion	Rare (BCR-ABL1 AML)	D,P	No	The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights^[25].
t(8;21)(q22;q22.1)	RUNX1- RUNX1T1	Rare (BCR-ABL1 AML)	D,P	No	The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights^[25].
t(15;17)(q13.4;q21.2)	PML-RARA	Rare (BCR-ABL1 AML)	D,P	No	The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights^[25].
AML-myelodysplasia-related (AML-MR) cytogenetic aberrations: • del(5q), t(5q) • inv(3)(q21q26) • ‐7, del(7q)	Unknown	Rare (BCR-ABL1 AML)	D,P	No	The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights^[25]. In AML, BCR-ABL appears to interact with specific aberrations like inv(16) and myelodysplasia-related cytogenetic changes, like del(5q), t(5q)^[25], inv(3)(q21q26)^[25], ‐7, del(7q)^[26], but the mechanisms of disease initiation and cooperation remain unclear^[5].

Gene Mutations (SNV/INDEL)

RUNX1 mutation is common in AML with BCR::ABL1 and occurs in ~40% of cases^[4]. Other mutated genes include ASXL1, BCOR, IDH1 / IDH2 and SRSF2; each of these occur in 10 - 15% of cases^[27]^[28]^[4].Coinciding molecular events such as NPM1 mutations have been reported^[25]. Mutations of FLT3 or DNMT3A are not commonly detected^[4].

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
RUNX1	Variable LOF and missense mutations	Tumor Suppressor Gene	Common (BCR-ABL1 AML)	D,P	No	AML with RUNX1 mutation is associated with a poorer prognosis^[8]. RUNX1 was the most commonly mutated gene, altered in eight of 21 BCR-ABL1 AML cases (38%)^[4]. Mutations in five genes (BCOR, BCORL1, SF3B1, SRSF2, and STAG2), along with ASXL1 and RUNX1 mutations, are linked to the proposed high-risk AML chromatin-spliceosome group^[4].
ASXL1	Variable LOF and missense mutations	Tumor Suppressor Gene	Recurrent (BCR-ABL1 AML)	D,P	No	Mutations in five genes (BCOR, BCORL1, SF3B1, SRSF2, and STAG2), along with ASXL1 and RUNX1 mutations, are linked to the proposed high-risk AML chromatin-spliceosome group^[4].
BCOR	Variable LOF and missense mutations	Tumor Suppressor Gene	Recurrent (BCR-ABL1 AML)	D,P	No	Mutations in five genes (BCOR, BCORL1, SF3B1, SRSF2, and STAG2), along with ASXL1 and RUNX1 mutations, are linked to the proposed high-risk AML chromatin-spliceosome group^[4].
IDH1 / IDH2	Missense	Oncogene	Recurrent (BCR-ABL1 AML)	D,P	No	Other mutated genes include ASXL1, BCOR, IDH1 / IDH2 and SRSF2; each of these occur in 10 - 15% of cases^[27]^[28]^[4].
SRSF2	Missense and in frame del	Tumor Suppressor Gene	Recurrent (BCR-ABL1 AML)	D,P	No	Mutations in five genes (BCOR, BCORL1, SF3B1, SRSF2, and STAG2), along with ASXL1 and RUNX1 mutations, are linked to the proposed high-risk AML chromatin-spliceosome group^[4].
NPM1	Variable LOF	Tumor Suppressor Gene and Oncogene	Rare (BCR-ABL1 AML)	D,P	No	Philadelphia-positive subclones can emerge in NPM1-mutated AML at diagnosis or during follow-up, and may cooperate with the NPM1 mutation like other class I mutations, such as FLT3-ITD or MLL-PTD^[25].

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

Not applicable

Genes and Main Pathways Involved

The BCR gene product has serine/threonine kinase activity and is a GTPase-activating protein for p21rac^[29]. The ABL1 gene is a proto-oncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of this protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene^[30]. The t(9,22)(q34;q11) leads to the formation of a Philadelphia chromosome and generates an active chimeric BCR-ABL1 tyrosine kinase. The fusion gene is created by juxtaposing the ABL1 gene on chromosome 9 (region q34) to a part of BCR (breakpoint cluster region) gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome, 22q-), the oncogenic BCR-ABL1 being found on the shorter derivative 22 chromosome^[31]^[32]. This gene encodes for a BCR-ABL1 fusion protein, a tyrosine kinase. Tyrosine kinase activities are typically regulated in an auto-inhibitory manner, but the BCR-ABL1 fusion gene codes for a protein that is continuously activated, causing unregulated cell division. This is a result of the replacement of the myristoylated cap region which causes a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein^[33]. The enzyme is responsible for the uncontrolled growth of leukemic cells which survive better than normal blood cells. As a result of BCR/ABL1 variable splicing (fusion RNA and hybrid proteins), two transcripts p190 and p210 are found for BCR-ABL1 positive AML.

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
BCR and ABL1; Activating mutations	Ras/MAPK, PI3K/AKT, JAK/STAT and NF-kappaB pathways	The BCR-ABL fusion protein is an constitutively active tyrosine kinase that triggers multiple pathways, promoting unchecked cell proliferation and survival.

Figure 1. Philadelphia chromosome. A piece of chromosome 9 and a piece of chrosomome 22 break off and trade places. The BCR-ABL1 gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called Philadelphia chromosome. Image from National Cancer Institute website https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bcr-abl-fusion-gene

Figure 2. Signal transduction pathway of the BCR-ABL fusion gene

Genetic Diagnostic Testing Methods

Bone marrow with myeloid blasts >20% combined with detection of t(9,22) by karyotype analysis or BCR-ABL1 using FISH or reverse transcriptase-quantitative PCR (RT-qPCR) and RNA or DNA seq^[5]. A graphic of the clinical path for the differential diagnosis of BCR-ABL1 positive acute myeloid leukemia and chronic myeloid leukemia-myeloid blast crisis (CML-MBC) is presented^[5].

Familial Forms

Not applicable

Additional Information

Not applicable

Links

ABL1

BCR

Vogel A, et al. Acute Myeloid Leukemia with BCR-ABL1. SH2017-0299. Presentation at Society for Hematopathology / European Association for Haematopathology (SH/EAHP) 2017 Workshop. https://www.sh-eahp.org/images/2017_Workshop/3_3SH-EAHP%202017_AML%20with%20BCR-ABL1_%20AV%20FINAL.pdf (accessed 29th June 2018)

References

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↑ Branford, Susan; et al. (2014-07-24). "Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline". Blood. 124 (4): 511–518. doi:10.1182/blood-2014-03-566323. ISSN 1528-0020. PMID 24859364.
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↑ ^16.0 ^16.1 Al Hamad, Mohammad (2021). "Contribution of BCR-ABL molecular variants and leukemic stem cells in response and resistance to tyrosine kinase inhibitors: a review". F1000Research. 10: 1288. doi:10.12688/f1000research.74570.2. ISSN 2046-1402. PMC 8886173 Check |pmc= value (help). PMID 35284066 Check |pmid= value (help).
↑ Tumours, 5th edition, IARC Press:Lyon, 2024. Online at: WHO Classification of Tumours.
↑ Shao, Xiaoyan; et al. (2018-11). "Primary Philadelphia chromosome positive acute myeloid leukemia: A case report". Medicine. 97 (44): e12949. doi:10.1097/MD.0000000000012949. ISSN 1536-5964. PMC 6221582. PMID 30383645. Check date values in: |date= (help)
↑ Lazarevic, Vladimir Lj; et al. (2018-01). "Relatively favorable outcome after allogeneic stem cell transplantation for BCR-ABL1-positive AML: A survey from the acute leukemia working party of the European Society for blood and marrow transplantation (EBMT)". American Journal of Hematology. 93 (1): 31–39. doi:10.1002/ajh.24928. ISSN 1096-8652. PMID 28971504. Check date values in: |date= (help)
↑ Konoplev, Sergej; et al. (2013-01). "Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia". Leukemia & Lymphoma. 54 (1): 138–144. doi:10.3109/10428194.2012.701739. ISSN 1029-2403. PMC 3925981. PMID 22691121. Check date values in: |date= (help)
↑ Nacheva, Ellie P.; et al. (2013). "Does BCR/ABL1 positive acute myeloid leukaemia exist?". British Journal of Haematology. 161 (4): 541–550. doi:10.1111/bjh.12301. ISSN 1365-2141. PMID 23521501.
↑ Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140.
↑ Jakovic, Ljubomir; et al. (2022-09-01). "De novo acute myeloid leukemia harboring concomitant t(8;21)(q22;q22);RUNX1::RUNX1T1 and BCR::ABL1 (p190 minor transcript)". Journal of Hematopathology. 15 (3): 191–195. doi:10.1007/s12308-022-00509-4. ISSN 1865-5785.
↑ Singh, Manish K.; et al. (2017-03-01). "Co-existence of AML1-ETO and BCR-ABL1 transcripts in a relapsed patient of acute myeloid leukemia with favorable risk group: A coincidence or clonal evolution?". Hematology/Oncology and Stem Cell Therapy. 10 (1): 39–41. doi:10.1016/j.hemonc.2015.12.003. ISSN 1658-3876.
↑ ^25.00 ^25.01 ^25.02 ^25.03 ^25.04 ^25.05 ^25.06 ^25.07 ^25.08 ^25.09 Bacher, Ulrike; et al. (2011). "Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations". British Journal of Haematology. 152 (6): 713–720. doi:10.1111/j.1365-2141.2010.08472.x. ISSN 1365-2141. PMID 21275954.
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Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

Kay Weng Choy MBBS, Monash Medical Centre

*Citation of this Page: “Acute myeloid leukaemia with BCR::ABL1 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 07/3/2025, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_BCR::ABL1_fusion.

[:3-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 Soupir, Chad P.; et al. (2007-04). "Philadelphia chromosome-positive acute myeloid leukemia: a rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis". American Journal of Clinical Pathology. 127 (4): 642–650. doi:10.1309/B4NVER1AJJ84CTUU. ISSN 0002-9173. PMID 17369142. Check date values in: |date= (help)

[:4-2] 2.0 ^2.1 ^2.2 Konoplev, Sergej; et al. (2013-01). "Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia". Leukemia & Lymphoma. 54 (1): 138–144. doi:10.3109/10428194.2012.701739. ISSN 1029-2403. PMC 3925981. PMID 22691121. Check date values in: |date= (help)

[3] Nacheva, Ellie P.; et al. (2013-05). "Does BCR/ABL1 positive acute myeloid leukaemia exist?". British Journal of Haematology. 161 (4): 541–550. doi:10.1111/bjh.12301. ISSN 1365-2141. PMID 23521501. Check date values in: |date= (help)

[:13-4] 4.00 ^4.01 ^4.02 ^4.03 ^4.04 ^4.05 ^4.06 ^4.07 ^4.08 ^4.09 Orsmark-Pietras, Christina; et al. (2021-06). "Clinical and genomic characterization of patients diagnosed with the provisional entity acute myeloid leukemia with BCR-ABL1, a Swedish population-based study". Genes, Chromosomes & Cancer. 60 (6): 426–433. doi:10.1002/gcc.22936. ISSN 1098-2264. PMID 33433047 Check |pmid= value (help). Check date values in: |date= (help)

[:2-5] 5.0 ^5.1 ^5.2 ^5.3 ^5.4 ^5.5 ^5.6 ^5.7 Neuendorff, Nina Rosa; et al. (2016). "BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features". Annals of Hematology. 95 (8): 1211–1221. doi:10.1007/s00277-016-2721-z. ISSN 1432-0584. PMID 27297971.

[:1-6] Arber DA, et al., (2017). Acute Myeloid Leukemia, in Hematopathology, 2nd Edition. Jaffe E, Arer DA, Campo E, Harris NL, and Quintanilla-Fend L, Editors. Elsevier:Philadelphia, PA, p817-846.

[7] Cuneo, A.; et al. (1996). "Philadelphia chromosome-positive acute myeloid leukemia: cytoimmunologic and cytogenetic features". Haematologica. 81 (5): 423–427. ISSN 0390-6078. PMID 8952155.

[:6-8] 8.0 ^8.1 ^8.2 Pollyea DA, Altman JK, (2025). NCCN Clinical Practice Guidelines in Oncology: AML. Version 2. Available at: NCCN.org.

[9] Maiti, Abhishek; et al. (2020). "Venetoclax and BCR-ABL Tyrosine Kinase Inhibitor Combinations: Outcome in Patients with Philadelphia Chromosome-Positive Advanced Myeloid Leukemias". Acta Haematologica. 143 (6): 567–573. doi:10.1159/000506346. ISSN 1421-9662. PMC 7839068 Check |pmc= value (help). PMID 32289808 Check |pmid= value (help).

[10] Cross, Nicholas C. P.; et al. (2023-11). "European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia". Leukemia. 37 (11): 2150–2167. doi:10.1038/s41375-023-02048-y. ISSN 1476-5551. PMC 10624636 Check |pmc= value (help). PMID 37794101 Check |pmid= value (help). Check date values in: |date= (help)

[11] Sawyers, C. L. (1999-04-29). "Chronic myeloid leukemia". The New England Journal of Medicine. 340 (17): 1330–1340. doi:10.1056/NEJM199904293401706. ISSN 0028-4793. PMID 10219069.

[12] Sharma, Diwakar; et al. (2024-08-01). "Does presence of complex translocations involving BCR::ABL1 in chronic myeloid leukemia affect the response rate to tyrosine kinase inhibitors? A systematic review of the literature". Annals of Diagnostic Pathology. 71: 152303. doi:10.1016/j.anndiagpath.2024.152303. ISSN 1092-9134.

[13] Cortes, Jorge E.; et al. (2003-05-15). "Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy". Blood. 101 (10): 3794–3800. doi:10.1182/blood-2002-09-2790. ISSN 0006-4971. PMID 12560227.

[14] Branford, Susan; et al. (2014-07-24). "Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline". Blood. 124 (4): 511–518. doi:10.1182/blood-2014-03-566323. ISSN 1528-0020. PMID 24859364.

[15] Lauseker, Michael; et al. (2023-11). "Survival with chronic myeloid leukaemia after failing milestones". Leukemia. 37 (11): 2231–2236. doi:10.1038/s41375-023-02028-2. ISSN 1476-5551. PMC 10624616 Check |pmc= value (help). PMID 37726340 Check |pmid= value (help). Check date values in: |date= (help)

[:5-16] 16.0 ^16.1 Al Hamad, Mohammad (2021). "Contribution of BCR-ABL molecular variants and leukemic stem cells in response and resistance to tyrosine kinase inhibitors: a review". F1000Research. 10: 1288. doi:10.12688/f1000research.74570.2. ISSN 2046-1402. PMC 8886173 Check |pmc= value (help). PMID 35284066 Check |pmid= value (help).

[17] Tumours, 5th edition, IARC Press:Lyon, 2024. Online at: WHO Classification of Tumours.

[18] Shao, Xiaoyan; et al. (2018-11). "Primary Philadelphia chromosome positive acute myeloid leukemia: A case report". Medicine. 97 (44): e12949. doi:10.1097/MD.0000000000012949. ISSN 1536-5964. PMC 6221582. PMID 30383645. Check date values in: |date= (help)

[19] Lazarevic, Vladimir Lj; et al. (2018-01). "Relatively favorable outcome after allogeneic stem cell transplantation for BCR-ABL1-positive AML: A survey from the acute leukemia working party of the European Society for blood and marrow transplantation (EBMT)". American Journal of Hematology. 93 (1): 31–39. doi:10.1002/ajh.24928. ISSN 1096-8652. PMID 28971504. Check date values in: |date= (help)

[20] Konoplev, Sergej; et al. (2013-01). "Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia". Leukemia & Lymphoma. 54 (1): 138–144. doi:10.3109/10428194.2012.701739. ISSN 1029-2403. PMC 3925981. PMID 22691121. Check date values in: |date= (help)

[21] Nacheva, Ellie P.; et al. (2013). "Does BCR/ABL1 positive acute myeloid leukaemia exist?". British Journal of Haematology. 161 (4): 541–550. doi:10.1111/bjh.12301. ISSN 1365-2141. PMID 23521501.

[:0-22] Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140.

[23] Jakovic, Ljubomir; et al. (2022-09-01). "De novo acute myeloid leukemia harboring concomitant t(8;21)(q22;q22);RUNX1::RUNX1T1 and BCR::ABL1 (p190 minor transcript)". Journal of Hematopathology. 15 (3): 191–195. doi:10.1007/s12308-022-00509-4. ISSN 1865-5785.

[24] Singh, Manish K.; et al. (2017-03-01). "Co-existence of AML1-ETO and BCR-ABL1 transcripts in a relapsed patient of acute myeloid leukemia with favorable risk group: A coincidence or clonal evolution?". Hematology/Oncology and Stem Cell Therapy. 10 (1): 39–41. doi:10.1016/j.hemonc.2015.12.003. ISSN 1658-3876.

[:12-25] 25.00 ^25.01 ^25.02 ^25.03 ^25.04 ^25.05 ^25.06 ^25.07 ^25.08 ^25.09 Bacher, Ulrike; et al. (2011). "Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations". British Journal of Haematology. 152 (6): 713–720. doi:10.1111/j.1365-2141.2010.08472.x. ISSN 1365-2141. PMID 21275954.

[26] Tirado, Carlos A.; et al. (2010-07). "Acute myeloid leukemia with inv(16) with CBFB–MYH11, 3′CBFB deletion, variant t(9;22) with BCR–ABL1, and del(7)(q22q32) in a pediatric patient: case report and literature review". Cancer Genetics and Cytogenetics. 200 (1): 54–59. doi:10.1016/j.cancergencyto.2010.03.001. ISSN 0165-4608. Check date values in: |date= (help)

[:14-27] 27.0 ^27.1 Konoplev, Sergej; et al. (2013-01). "Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia". Leukemia & Lymphoma. 54 (1): 138–144. doi:10.3109/10428194.2012.701739. ISSN 1029-2403. PMC 3925981. PMID 22691121. Check date values in: |date= (help)

[:15-28] 28.0 ^28.1 Eisfeld, A.-K.; et al. (2017-10). "The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia". Leukemia. 31 (10): 2211–2218. doi:10.1038/leu.2017.86. ISSN 1476-5551. PMC 5628133. PMID 28321123. Check date values in: |date= (help)

[:7-29] Maru, Y.; et al. (1991). "The BCR gene encodes a novel serine/threonine kinase activity within a single exon". Cell. 67 (3): 459–468. doi:10.1016/0092-8674(91)90521-y. ISSN 0092-8674. PMID 1657398.

[:8-30] Wang, Jean Y. J. (2014). "The capable ABL: what is its biological function?". Molecular and Cellular Biology. 34 (7): 1188–1197. doi:10.1128/MCB.01454-13. ISSN 1098-5549. PMC 3993570. PMID 24421390.

[:9-31] Kurzrock, Razelle; et al. (2003). "Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics". Annals of Internal Medicine. 138 (10): 819–830. doi:10.7326/0003-4819-138-10-200305200-00010. ISSN 1539-3704. PMID 12755554.

[:10-32] Melo, J. V. (1996). "The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype". Blood. 88 (7): 2375–2384. ISSN 0006-4971. PMID 8839828.

[:11-33] Nagar, Bhushan; et al. (2003). "Structural basis for the autoinhibition of c-Abl tyrosine kinase". Cell. 112 (6): 859–871. doi:10.1016/s0092-8674(03)00194-6. ISSN 0092-8674. PMID 12654251.

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HAEM5:Acute myeloid leukaemia with BCR::ABL1 fusion: Difference between revisions

Latest revision as of 12:06, 3 July 2025

Contents

Primary Author(s)*

WHO Classification of Disease

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDEL)

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

Additional Information

Links

References

Notes

Navigation menu

@@ Line 35: / Line 35: @@
 |}
-==WHO Essential and Desirable Genetic Diagnostic Criteria==
-<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
-{| class="wikitable"
-|+
-|WHO Essential Criteria (Genetics)*
-|a myeloid neoplasm with >20% blasts expressing a myeloid immunophenotype in the bone marrow and/or peripheral blood; detection of ''BCR::ABL1'' at initial diagnosis; lack of features of CML before or at diagnosis or after therapy.
-|-
-|WHO Desirable Criteria (Genetics)*
-|presence of t(9;22)(q34;q11.2) on conventional karyotyping; determination of the ''BCR::ABL1'' transcript subtype and establishment of a baseline level of ''BCR::ABL1'' transcript subtype and establishment of a baseline level of ''BCR::ABL1'' transcript for monitoring treatment response.
-|-
-|Other Classification
-|
-|}
-<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
 ==Related Terminology==
-<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
 {| class="wikitable"
 |+
 |Acceptable
-|acute myeloid leukaemia with t(9;22)(q34;q11.2)
+|Acute myeloid leukaemia with t(9;22)(q34;q11.2)
 |-
 |Not Recommended
-|
+|N/A
 |}
@@ Line 63: / Line 49: @@
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
+The t(9:22)(q34.1;q11.2) results in the formation of the Ph chromosome and the chimeric BCR-ABL1 fusion gene. In AML, ~70 - 80% cases with ''BCR::ABL1'' harbor p210 transcripts, and 50-60% cases with additional chromosomal abnormalities<ref name=":3">{{Cite journal|last=Soupir|first=Chad P.|last2=Vergilio|first2=Jo-Anne|last3=Dal Cin|first3=Paola|last4=Muzikansky|first4=Alona|last5=Kantarjian|first5=Hagop|last6=Jones|first6=Dan|last7=Hasserjian|first7=Robert P.|date=2007-04|title=Philadelphia chromosome-positive acute myeloid leukemia: a rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis|url=https://pubmed.ncbi.nlm.nih.gov/17369142|journal=American Journal of Clinical Pathology|volume=127|issue=4|pages=642–650|doi=10.1309/B4NVER1AJJ84CTUU|issn=0002-9173|pmid=17369142}}</ref><ref name=":4">{{Cite journal|last=Konoplev|first=Sergej|last2=Yin|first2=C. Cameron|last3=Kornblau|first3=Steven M.|last4=Kantarjian|first4=Hagop M.|last5=Konopleva|first5=Marina|last6=Andreeff|first6=Michael|last7=Lu|first7=Gary|last8=Zuo|first8=Zhuang|last9=Luthra|first9=Rajyalakshmi|date=2013-01|title=Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22691121|journal=Leukemia & Lymphoma|volume=54|issue=1|pages=138–144|doi=10.3109/10428194.2012.701739|issn=1029-2403|pmc=3925981|pmid=22691121}}</ref><ref>{{Cite journal|last=Nacheva|first=Ellie P.|last2=Grace|first2=Colin D.|last3=Brazma|first3=Diana|last4=Gancheva|first4=Katya|last5=Howard-Reeves|first5=Julie|last6=Rai|first6=Lena|last7=Gale|first7=Rosemary E.|last8=Linch|first8=David C.|last9=Hills|first9=Robert K.|date=2013-05|title=Does BCR/ABL1 positive acute myeloid leukaemia exist?|url=https://pubmed.ncbi.nlm.nih.gov/23521501|journal=British Journal of Haematology|volume=161|issue=4|pages=541–550|doi=10.1111/bjh.12301|issn=1365-2141|pmid=23521501}}</ref><ref name=":13">{{Cite journal|last=Orsmark-Pietras|first=Christina|last2=Landberg|first2=Niklas|last3=Lorenz|first3=Fryderyk|last4=Uggla|first4=Bertil|last5=Höglund|first5=Martin|last6=Lehmann|first6=Sören|last7=Derolf|first7=Åsa|last8=Deneberg|first8=Stefan|last9=Antunovic|first9=Petar|date=2021-06|title=Clinical and genomic characterization of patients diagnosed with the provisional entity acute myeloid leukemia with BCR-ABL1, a Swedish population-based study|url=https://pubmed.ncbi.nlm.nih.gov/33433047|journal=Genes, Chromosomes & Cancer|volume=60|issue=6|pages=426–433|doi=10.1002/gcc.22936|issn=1098-2264|pmid=33433047}}</ref>.  The most common BCR-ABL1 transcripts p190 and p210 have been detected in nearly equal distribution<ref name=":2">{{Cite journal|last=Neuendorff|first=Nina Rosa|last2=Burmeister|first2=Thomas|last3=Dörken|first3=Bernd|last4=Westermann|first4=Jörg|date=2016|title=BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features|url=https://www.ncbi.nlm.nih.gov/pubmed/27297971|journal=Annals of Hematology|volume=95|issue=8|pages=1211–1221|doi=10.1007/s00277-016-2721-z|issn=1432-0584|pmid=27297971}}</ref>. Since p190 is very rare in CML (p210 transcripts in >99% of cases), the presentation with a p190 transcript is in favor of the diagnosis of AML rather than CML<ref name=":1">Arber DA, et al., (2017). Acute Myeloid Leukemia, in Hematopathology, 2nd Edition. Jaffe E, Arer DA, Campo E, Harris NL, and Quintanilla-Fend L, Editors. Elsevier:Philadelphia, PA, p817-846.</ref>.
 {| class="wikitable sortable"
 |-
@@ Line 72: / Line 58: @@
 !Clinical Relevance Details/Other Notes
 |-
-|''ABL1''||''BCR::ABL1''||The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||t(9;22)(q34;q11.2)
+|''ABL1''||''BCR::ABL1''||The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.
-|Common (CML)
+|t(9;22)(q34;q11.2)
-|D, P, T
+|Common (CML); Rare (AML).<!-- The new version WHO indicates BCR::ABL1 is rare in AML, only accounts less than 0.5%, but the literature I found typically is 0.5-3%, the previous version also indicates the prevalence is <3%. Pls advice which number I should use. -->
+|Diagnosis: BCR-ABL1 positive AML is an emerging entity. The proliferation of ''BCR-ABL1'' positive blasts present a diagnostic dilemma. While it may be difficult, it is essential to distinguish between BCR-ABL1 positive AML and Chronic Myeloid Leukemia in Myeloid Blast Crisis (CML-MBC), in order to choose the most appropriate therapy (e.g., intensive induction chemotherapy versus tyrosine kinase inhibitor (TKI) followed by an early allogeneic stem cell transplant). After the exclusion of acute leukemia of ambiguous lineage (a separate entity according to WHO) by flow cytometry, it is helpful to note any past history of antecedent hematological disease. Compared to CML-MBC, a higher percentage of blasts (median: 47% vs 13%), a lower percentage of basophils (median: 0% vs 2.5%) and absolute basophil count, a lower frequency of splenomegaly (25% vs 65%), lower cellularity, fewer dwarf megakaryocytes, and normal M:E ratio favor the diagnosis of BCR-ABL1 positive AML<ref name=":4" /><ref name=":3" />. The detection of p190 transcript and the occurrence of any BCR-ABL1 transcript in less than 100% of metaphases supports the diagnosis of AML rather than CML. Persistent CCyR (Complete Cytogenetic Response) after conventional chemotherapy is unusual for CML-MBC and supports the diagnosis of BCR-ABL1 positive AML<ref name=":2" />. Karyotype analysis that identifies the t(9;22)(q34;q11.2) translocation, either alone or in conjunction with additional chromosomal abnormalities, characterizes BCR-ABL1 positive AML<ref name=":3" /><ref name=":4" />. In addition, molecular methods including dual-colour dual-fusion FISH, RT-PCR, qPCR, and RNA or DNA sequencing are used to identify all common breakpoint variants when applicable.
+Prognosis: The overall prognosis of BCR-ABL1 positive AML is poor, with a median survival time of <9 months<ref>{{Cite journal|last=Cuneo|first=A.|last2=Ferrant|first2=A.|last3=Michaux|first3=J. L.|last4=Demuynck|first4=H.|last5=Boogaerts|first5=M.|last6=Louwagie|first6=A.|last7=Doyen|first7=C.|last8=Stul|first8=M.|last9=Cassiman|first9=J. J.|date=1996|title=Philadelphia chromosome-positive acute myeloid leukemia: cytoimmunologic and cytogenetic features|url=https://pubmed.ncbi.nlm.nih.gov/8952155|journal=Haematologica|volume=81|issue=5|pages=423–427|issn=0390-6078|pmid=8952155}}</ref><ref name=":3" />. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for AML categorize this entity into the poor-risk group, comparable with complex aberrant karyotype AML<ref name=":6">Pollyea DA, Altman JK, (2025). NCCN Clinical Practice Guidelines in Oncology: AML. Version 2. Available at: NCCN.org.</ref>. It appears that the prognosis of BCR-ABL1 positive AML depends more on the genetic background (concurrent aberrations) than on BCR-ABL1 itself. Unlike in CML, BCR-ABL1 does not appear to be the key driver in AML though may provide a proliferative advantage to a particular BCR-ABL1 positive subclone.
+Therapeutics: There is currently no standardized treatment approach for BCR-ABL1 positive AML. Therapy with TKI alone does not produce sustained responses in BCR-ABL1 positive AML<ref name=":3" />. This may be due to a very rapid clonal evolution, resulting in resistance in a much higher proportion of patients and in a significantly shorter time than in CML<ref name=":2" />.Venetoclax and TKI combination regimens have shown good response in some studies<ref>{{Cite journal|last=Maiti|first=Abhishek|last2=Franquiz|first2=Miguel J.|last3=Ravandi|first3=Farhad|last4=Cortes|first4=Jorge E.|last5=Jabbour|first5=Elias J.|last6=Sasaki|first6=Koji|last7=Marx|first7=Kayleigh|last8=Daver|first8=Naval G.|last9=Kadia|first9=Tapan M.|date=2020|title=Venetoclax and BCR-ABL Tyrosine Kinase Inhibitor Combinations: Outcome in Patients with Philadelphia Chromosome-Positive Advanced Myeloid Leukemias|url=https://pubmed.ncbi.nlm.nih.gov/32289808|journal=Acta Haematologica|volume=143|issue=6|pages=567–573|doi=10.1159/000506346|issn=1421-9662|pmc=7839068|pmid=32289808}}</ref>.
 |Yes (WHO, NCCN)
-|The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
+|The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context<ref>{{Cite journal|last=Cross|first=Nicholas C. P.|last2=Ernst|first2=Thomas|last3=Branford|first3=Susan|last4=Cayuela|first4=Jean-Michel|last5=Deininger|first5=Michael|last6=Fabarius|first6=Alice|last7=Kim|first7=Dennis Dong Hwan|last8=Machova Polakova|first8=Katerina|last9=Radich|first9=Jerald P.|date=2023-11|title=European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/37794101|journal=Leukemia|volume=37|issue=11|pages=2150–2167|doi=10.1038/s41375-023-02048-y|issn=1476-5551|pmc=10624636|pmid=37794101}}</ref><ref>{{Cite journal|last=Sawyers|first=C. L.|date=1999-04-29|title=Chronic myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10219069|journal=The New England Journal of Medicine|volume=340|issue=17|pages=1330–1340|doi=10.1056/NEJM199904293401706|issn=0028-4793|pmid=10219069}}</ref>. The prevalence of BCR"" ABL1 in CML is common ~90-95%<ref>{{Cite journal|last=Sharma|first=Diwakar|last2=Wilson|first2=Christine|last3=Kumar|first3=Sachin|last4=Ghose|first4=Sampa|last5=Sahoo|first5=Ranjit|last6=Sharawat|first6=Surender K.|date=2024-08-01|title=Does presence of complex translocations involving BCR::ABL1 in chronic myeloid leukemia affect the response rate to tyrosine kinase inhibitors? A systematic review of the literature|url=https://linkinghub.elsevier.com/retrieve/pii/S1092913424000406|journal=Annals of Diagnostic Pathology|volume=71|pages=152303|doi=10.1016/j.anndiagpath.2024.152303|issn=1092-9134}}</ref>. This fusion is responsive to targeted therapy such as Imatinib (Gleevec)<ref>{{Cite journal|last=Cortes|first=Jorge E.|last2=Talpaz|first2=Moshe|last3=Giles|first3=Francis|last4=O'Brien|first4=Susan|last5=Rios|first5=Mary Beth|last6=Shan|first6=Jianqin|last7=Garcia-Manero|first7=Guillermo|last8=Faderl|first8=Stefan|last9=Thomas|first9=Deborah A.|date=2003-05-15|title=Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy|url=https://pubmed.ncbi.nlm.nih.gov/12560227|journal=Blood|volume=101|issue=10|pages=3794–3800|doi=10.1182/blood-2002-09-2790|issn=0006-4971|pmid=12560227}}</ref>.
-|}
-<blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
-The t(9:22)(q34.1;q11.2) results in the formation of the Ph chromosome and the chimeric BCR-ABL1 fusion gene. In AML, the most common BCR-ABL1 transcripts p190 and p210 have been detected in nearly equal distribution<ref name=":2">{{Cite journal|last=Neuendorff|first=Nina Rosa|last2=Burmeister|first2=Thomas|last3=Dörken|first3=Bernd|last4=Westermann|first4=Jörg|date=2016|title=BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features|url=https://www.ncbi.nlm.nih.gov/pubmed/27297971|journal=Annals of Hematology|volume=95|issue=8|pages=1211–1221|doi=10.1007/s00277-016-2721-z|issn=1432-0584|pmid=27297971}}</ref>. Since p190 is very rare in CML (p210 transcripts in >99% of cases), the presentation with a p190 transcript is in favour of the diagnosis of AML rather than CML<ref name=":1">Arber DA, et al., (2017). Acute Myeloid Leukemia, in Hematopathology, 2nd Edition. Jaffe E, Arer DA, Campo E, Harris NL, and Quintanilla-Fend L, Editors. Elsevier:Philadelphia, PA, p817-846.</ref>.
+BCR::ABL1 is generally favorable in CML<ref>{{Cite journal|last=Branford|first=Susan|last2=Yeung|first2=David T.|last3=Parker|first3=Wendy T.|last4=Roberts|first4=Nicola D.|last5=Purins|first5=Leanne|last6=Braley|first6=Jodi A.|last7=Altamura|first7=Haley K.|last8=Yeoman|first8=Alexandra L.|last9=Georgievski|first9=Jasmina|date=2014-07-24|title=Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline|url=https://pubmed.ncbi.nlm.nih.gov/24859364|journal=Blood|volume=124|issue=4|pages=511–518|doi=10.1182/blood-2014-03-566323|issn=1528-0020|pmid=24859364}}</ref><ref>{{Cite journal|last=Lauseker|first=Michael|last2=Hehlmann|first2=Rüdiger|last3=Hochhaus|first3=Andreas|last4=Saußele|first4=Susanne|date=2023-11|title=Survival with chronic myeloid leukaemia after failing milestones|url=https://pubmed.ncbi.nlm.nih.gov/37726340|journal=Leukemia|volume=37|issue=11|pages=2231–2236|doi=10.1038/s41375-023-02028-2|issn=1476-5551|pmc=10624616|pmid=37726340}}</ref>.
-{| class="wikitable sortable"
+Three BCR-ABL chimeric proteins result from varying mRNA fusions of the ABL and BCR genes. The most common breakpoint occurs in BCR intron 13 or 14, fusing to ABL1 exon a2 (e13a2, e14a2), yielding a 210 kilodalton protein (p210 BCR-ABL1) found in 95% of CML cases. A rare alternative (<1%) is the e19a2 fusion, producing a 230 kilodalton protein (p230 BCR-ABL1), a marker for neutrophilic-chronic myeloid leukemia. The e1a2 fusion results in the p190 BCR-ABL1 protein, prevalent in B cell ALL, less common in AML, and rare in CML<ref name=":5">{{Cite journal|last=Al Hamad|first=Mohammad|date=2021|title=Contribution of BCR-ABL molecular variants and leukemic stem cells in response and resistance to tyrosine kinase inhibitors: a review|url=https://pubmed.ncbi.nlm.nih.gov/35284066|journal=F1000Research|volume=10|pages=1288|doi=10.12688/f1000research.74570.2|issn=2046-1402|pmc=8886173|pmid=35284066}}</ref>.
-|-
-!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
-|-
-|t(9;22)(q34;q11.2)||3'ABL1 / 5'BCR||der(22)||<3% of AML
-|}
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
+The prevalence of BCR::ABL1 in AML is rare (~0.5 - 3%)<ref name=":5" />, per 5th WHO guideline the prevalence is <0.5%<ref>Tumours, 5th edition, IARC Press:Lyon, 2024. Online at: WHO Classification of Tumours.</ref>.
-<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
+There is a single case report of an AML patient with BCR::ABL1 achieving molecular remission with dasatinib and chemotherapy<ref>{{Cite journal|last=Shao|first=Xiaoyan|last2=Chen|first2=Dangui|last3=Xu|first3=Peipei|last4=Peng|first4=Miaoxin|last5=Guan|first5=Chaoyang|last6=Xie|first6=Pinhao|last7=Yuan|first7=Cuiying|last8=Chen|first8=Bing|date=2018-11|title=Primary Philadelphia chromosome positive acute myeloid leukemia: A case report|url=https://pubmed.ncbi.nlm.nih.gov/30383645|journal=Medicine|volume=97|issue=44|pages=e12949|doi=10.1097/MD.0000000000012949|issn=1536-5964|pmc=6221582|pmid=30383645}}</ref>.
-* Chromosomal Rearrangements (Gene Fusions)
-* Individual Region Genomic Gain/Loss/LOH
-* Characteristic Chromosomal Patterns
-* Gene Mutations (SNV/INDEL)}}</blockquote>
-BCR-ABL1 positive AML is an emerging entity. The proliferation of BCR-ABL1 positive blasts present a diagnostic dilemma. While it may be difficult, it is essential to distinguish between BCR-ABL1 positive AML and CML-MBC, in order to choose the most appropriate therapy (e.g., intensive induction chemotherapy versus tyrosine kinase inhibitor (TKI) followed by an early allogeneic stem cell transplant). After the exclusion of acute leukemia of ambiguous lineage (a separate entity according to WHO) by flow cytometry, it is helpful to note any past history of antecedent hematological disease. Absence of basophilia and absence of splenomegaly favour the diagnosis of BCR-ABL1 positive AML (over CML-MBC). The detection of p190 transcript and the occurrence of any BCR-ABL1 transcript in less than 100% of metaphases supports the diagnosis of AML rather than CML. Persistent CCyR (Complete Cytogenetic Response) after conventional chemotherapy is unusual for CML-MBC and supports the diagnosis of BCR-ABL1 positive AML<ref name=":2" />.
-The overall prognosis of BCR-ABL1 positive AML is generally unfavourable. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for AML categorise this entity into the poor-risk group, comparable with complex aberrant karyotype AML<ref>O’Donnell MR, Tallman MS, (2016). NCCN Clinical Practise Guidelines in Oncology: AML. Version 1. Available at: NCCN.org.</ref>. It appears that the prognosis of BCR-ABL1 positive AML depends more on the genetic background (concurrent aberrations) than on BCR-ABL1 itself. Unlike in CML, BCR-ABL1 does not appear to be the key driver in AML though may provide a proliferative advantage to a particular BCR-ABL1 positive subclone There is currently no standardized treatment approach for BCR-ABL1 positive AML. Therapy with TKI alone does not produce sustained responses in BCR-ABL1 positive AML. This may be due to a very rapid clonal evolution, resulting in resistance in a much higher proportion of patients and in a significantly shorter time than in CML<ref name=":2" />.
+Outcome of patients < 50 years of age with TKI pretreated ''BCR::ABL1'' positive AML receiving allogeneic stem cell transplant is relatively favorable<ref>{{Cite journal|last=Lazarevic|first=Vladimir Lj|last2=Labopin|first2=Myriam|last3=Depei|first3=Wu|last4=Yakoub-Agha|first4=Ibrahim|last5=Huynh|first5=Anne|last6=Ljungman|first6=Per|last7=Schaap|first7=Nicolaas|last8=Cornelissen|first8=Jan J.|last9=Maillard|first9=Natacha|date=2018-01|title=Relatively favorable outcome after allogeneic stem cell transplantation for BCR-ABL1-positive AML: A survey from the acute leukemia working party of the European Society for blood and marrow transplantation (EBMT)|url=https://pubmed.ncbi.nlm.nih.gov/28971504|journal=American Journal of Hematology|volume=93|issue=1|pages=31–39|doi=10.1002/ajh.24928|issn=1096-8652|pmid=28971504}}</ref>.
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Individual Region Genomic Gain/Loss/LOH==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
+Survival status postallogeneic transplantation appears similar to intermediate risk AML, with one report demonstrating 3 year overall survival of 73%<ref>{{Cite journal|last=Konoplev|first=Sergej|last2=Yin|first2=C. Cameron|last3=Kornblau|first3=Steven M.|last4=Kantarjian|first4=Hagop M.|last5=Konopleva|first5=Marina|last6=Andreeff|first6=Michael|last7=Lu|first7=Gary|last8=Zuo|first8=Zhuang|last9=Luthra|first9=Rajyalakshmi|date=2013-01|title=Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22691121|journal=Leukemia & Lymphoma|volume=54|issue=1|pages=138–144|doi=10.3109/10428194.2012.701739|issn=1029-2403|pmc=3925981|pmid=22691121}}</ref>.
-{| class="wikitable sortable"
-|-
-!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
-!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
-!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
-!'''Clinical Relevance Details/Other Notes'''
-|-
-|<span class="blue-text">EXAMPLE:</span>
-|<span class="blue-text">EXAMPLE:</span> Loss
-|<span class="blue-text">EXAMPLE:</span>
-chr7
-|<span class="blue-text">EXAMPLE:</span>
-Unknown
-|<span class="blue-text">EXAMPLE:</span> D, P
-|<span class="blue-text">EXAMPLE:</span> No
-|<span class="blue-text">EXAMPLE:</span>
-Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
-|-
-|<span class="blue-text">EXAMPLE:</span>
-|<span class="blue-text">EXAMPLE:</span> Gain
-|<span class="blue-text">EXAMPLE:</span>
-chr8
-|<span class="blue-text">EXAMPLE:</span>
-Unknown
-|<span class="blue-text">EXAMPLE:</span> D, P
-|
-|<span class="blue-text">EXAMPLE:</span>
-Common recurrent secondary finding for t(8;21) (add references).
-|-
-|<span class="blue-text">EXAMPLE:</span>
-|<span class="blue-text">EXAMPLE:</span> Amp
-|<span class="blue-text">EXAMPLE:</span>
-q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
-|<span class="blue-text">EXAMPLE:</span>
-''ERBB2''
-|<span class="blue-text">EXAMPLE:</span> D, P, T
-|
-|<span class="blue-text">EXAMPLE:</span>
-Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
-|-
-|
-|
-|
-|
-|
-|
-|
 |}
+==Individual Region Genomic Gain/Loss/LOH==
-<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
-AML with BCR-ABL1 carries unique genome imbalances. Nacheva et al., used array comparative genomic hybridisation (CGH) to perform a comparative study between several BCR-ABL1 positive entities. BCR-ABL1 positive AML displays characteristic of lymphoid disease (found in BCR-ABL1 positive ALL and CML): deletions of ''IKZF1'' and/or ''CDKN2A/B'' genes were recurrent findings in BCR-ABL1 positive AML as well as cryptic deletions within the immunoglobulin ''IGH'' and T cell receptor gene (''TRG alpha'') complexes<ref>{{Cite journal|last=Nacheva|first=Ellie P.|last2=Grace|first2=Colin D.|last3=Brazma|first3=Diana|last4=Gancheva|first4=Katya|last5=Howard-Reeves|first5=Julie|last6=Rai|first6=Lena|last7=Gale|first7=Rosemary E.|last8=Linch|first8=David C.|last9=Hills|first9=Robert K.|date=2013|title=Does BCR/ABL1 positive acute myeloid leukaemia exist?|url=https://www.ncbi.nlm.nih.gov/pubmed/23521501|journal=British Journal of Haematology|volume=161|issue=4|pages=541–550|doi=10.1111/bjh.12301|issn=1365-2141|pmid=23521501}}</ref>. Importantly, these aberrations were found to be absent in CML-MBC and hence they are potentially a helpful diagnostic tool for difficult cases.
-Most cases will have monosomy 7, trisomy 8 or complex karyotypes in addition to the t(9;22)(q34.1;q11.2)<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140.</ref>.
+AML with BCR-ABL1 carries unique genome imbalances. Nacheva et al., used array comparative genomic hybridization (CGH) to perform a comparative study between several BCR-ABL1 positive entities. BCR-ABL1 positive AML displays characteristic of lymphoid disease (found in BCR-ABL1 positive ALL and CML): deletions of ''IKZF1'' and/or ''CDKN2A/B'' genes were recurrent findings in BCR-ABL1 positive AML as well as cryptic deletions within the immunoglobulin ''IGH'' and T cell receptor gene (''TRG alpha'') complexes<ref>{{Cite journal|last=Nacheva|first=Ellie P.|last2=Grace|first2=Colin D.|last3=Brazma|first3=Diana|last4=Gancheva|first4=Katya|last5=Howard-Reeves|first5=Julie|last6=Rai|first6=Lena|last7=Gale|first7=Rosemary E.|last8=Linch|first8=David C.|last9=Hills|first9=Robert K.|date=2013|title=Does BCR/ABL1 positive acute myeloid leukaemia exist?|url=https://www.ncbi.nlm.nih.gov/pubmed/23521501|journal=British Journal of Haematology|volume=161|issue=4|pages=541–550|doi=10.1111/bjh.12301|issn=1365-2141|pmid=23521501}}</ref>. Importantly, these aberrations were found to be absent in CML-MBC and hence they are potentially a helpful diagnostic tool for difficult cases.
+Most cases will have monosomy 7/Del(7q), trisomy 8 or complex karyotypes in addition to the t(9;22)(q34.1;q11.2)<ref name=":0">Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140.</ref>.
 {| class="wikitable sortable"
 |-
-!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
+!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
+!Clinical Relevance Details/Other Notes
 |-
-|7||Loss||chr7
+|7
+|Loss
+|chr7
+|''IKZF1,'' TR Beta Chain (TRB) genes<!-- Pls advice if this is correct, thx -->
+|D,P
+|No
+|Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML<ref name=":6" />.
 |-
-|8||Gain||chr8
+|8
-|}
+|Gain
+|chr8
-<blockquote class="blockedit">
+|Unknown
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
+|D,P
-----
+|No
-</blockquote>
+|Common recurrent secondary finding for t(8;21)<ref>{{Cite journal|last=Jakovic|first=Ljubomir|last2=Fekete|first2=Marija Dencic|last3=Virijevic|first3=Marijana|last4=Kurtovic|first4=Nada Kraguljac|last5=Todoric-Zivanovic|first5=Biljana|last6=Stamatovic|first6=Dragana|last7=Karan-Djurasevic|first7=Teodora|last8=Pavlovic|first8=Sonja|last9=Lekovic|first9=Danijela|date=2022-09-01|title=De novo acute myeloid leukemia harboring concomitant t(8;21)(q22;q22);RUNX1::RUNX1T1 and BCR::ABL1 (p190 minor transcript)|url=https://link.springer.com/article/10.1007/s12308-022-00509-4|journal=Journal of Hematopathology|language=en|volume=15|issue=3|pages=191–195|doi=10.1007/s12308-022-00509-4|issn=1865-5785}}</ref><ref>{{Cite journal|last=Singh|first=Manish K.|last2=Gupta|first2=Ruchi|last3=Rahman|first3=Khaliqur|last4=Kumar|first4=Sanjeev|last5=Sharma|first5=Akhilesh|last6=Nityanand|first6=Soniya|date=2017-03-01|title=Co-existence of AML1-ETO and BCR-ABL1 transcripts in a relapsed patient of acute myeloid leukemia with favorable risk group: A coincidence or clonal evolution?|url=https://www.sciencedirect.com/science/article/pii/S1658387616000054|journal=Hematology/Oncology and Stem Cell Therapy|volume=10|issue=1|pages=39–41|doi=10.1016/j.hemonc.2015.12.003|issn=1658-3876}}</ref>.
+|}<br />
 ==Characteristic Chromosomal or Other Global Mutational Patterns==
-Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
+Additional chromosomal aberrations are infrequently seen in BCR-ABL AML, it has been described together with different class II aberrations such as CBFB-MYH11, RUNX1- RUNX1T1 and PML-RARA<ref name=":12" /><ref name=":2" />. In AML, BCR-ABL1 seems to cooperate with several AML-specific aberrations such as inv(16), t(8;21) and myelodysplasia-related cytogenetic aberrations<ref name=":2" /><ref name=":12">{{Cite journal|last=Bacher|first=Ulrike|last2=Haferlach|first2=Torsten|last3=Alpermann|first3=Tamara|last4=Zenger|first4=Melanie|last5=Hochhaus|first5=Andreas|last6=Beelen|first6=Dietrich W.|last7=Uppenkamp|first7=Michael|last8=Rummel|first8=Mathias|last9=Kern|first9=Wolfgang|date=2011|title=Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations|url=https://www.ncbi.nlm.nih.gov/pubmed/21275954|journal=British Journal of Haematology|volume=152|issue=6|pages=713–720|doi=10.1111/j.1365-2141.2010.08472.x|issn=1365-2141|pmid=21275954}}</ref>. (For diagnostic purpose, note that inv(16) is not restricted to AML and can also be found in CML-MBC). Additional chromosomal aberrations, such as an additional Ph chromosome, trisomy 19 and isochromosome 17q seen in CML MBP are infrequently seen in AML with ''BCR::ABL1.''<!-- how to align left???  -->
 {| class="wikitable sortable"
 |-
 !Chromosomal Pattern
 !Molecular Pathogenesis
-!'''Prevalence -'''
+!Prevalence -
-'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
+Common >20%, Recurrent 5-20% or Rare <5% (Disease)
-!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
-!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
-!'''Clinical Relevance Details/Other Notes'''
+!Clinical Relevance Details/Other Notes
 |-
-|<span class="blue-text">EXAMPLE:</span>
+|inv(16)(p13.1q22) or t(16;16)(p13.1;q22)
-Co-deletion of 1p and 18q
+|CBFB::MYH11 fusion
-|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
+|Rare (BCR-ABL1 AML)
-|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
+|D,P
-|<span class="blue-text">EXAMPLE:</span> D, P
+|No<!-- Here, is it for Inv(16) in BCR-ABL1 patient or in all AML patients? -->
-|
+|The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights<ref name=":12" />.
-|
 |-
-|<span class="blue-text">EXAMPLE:</span>
+|t(8;21)(q22;q22.1)
-Microsatellite instability - hypermutated
+|RUNX1- RUNX1T1
-|
+|Rare (BCR-ABL1 AML)
-|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
+|D,P
-|<span class="blue-text">EXAMPLE:</span> P, T
+|No
-|
+|The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights<ref name=":12" />.
-|
 |-
-|
+|t(15;17)(q13.4;q21.2)
-|
+|PML-RARA
-|
+|Rare (BCR-ABL1 AML)
-|
+|D,P
-|
+|No
-|
+|The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights<ref name=":12" />.
-|}
+|-
+|AML-myelodysplasia-related (AML-MR) cytogenetic aberrations:
+• del(5q), t(5q)
-<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
+• inv(3)(q21q26)
-In AML, BCR-ABL1 has been described together with different class II aberrations such as CBFB-MYH11, RUNX1- RUNX1T1 and PML-RARA<ref name=":2" />. In AML, BCR-ABL1 seems to cooperate with several AML-specific aberrations such as inv(16), t(8;21) and myelodysplasia-related cytogenetic aberrations<ref name=":2" /><ref>{{Cite journal|last=Bacher|first=Ulrike|last2=Haferlach|first2=Torsten|last3=Alpermann|first3=Tamara|last4=Zenger|first4=Melanie|last5=Hochhaus|first5=Andreas|last6=Beelen|first6=Dietrich W.|last7=Uppenkamp|first7=Michael|last8=Rummel|first8=Mathias|last9=Kern|first9=Wolfgang|date=2011|title=Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations|url=https://www.ncbi.nlm.nih.gov/pubmed/21275954|journal=British Journal of Haematology|volume=152|issue=6|pages=713–720|doi=10.1111/j.1365-2141.2010.08472.x|issn=1365-2141|pmid=21275954}}</ref>. (For diagnostic purpose, note that inv(16) is not restricted to AML and can also be found in CML-MBC).
+• ‐7, del(7q)
+|Unknown
+|Rare (BCR-ABL1 AML)
+|D,P
+|No
+|The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights<ref name=":12" />.
-<blockquote class="blockedit">
+In AML, BCR-ABL appears to interact with specific aberrations like inv(16) and myelodysplasia-related cytogenetic changes, like del(5q), t(5q)<ref name=":12" />, inv(3)(q21q26)<ref name=":12" />, ‐7, del(7q)<ref>{{Cite journal|last=Tirado|first=Carlos A.|last2=Valdez|first2=Federico|last3=Klesse|first3=Laura|last4=Karandikar|first4=Nitin J.|last5=Uddin|first5=Naseem|last6=Arbini|first6=Arnaldo|last7=Fustino|first7=Nicholas|last8=Collins|first8=Robert|last9=Patel|first9=Sangeeta|date=2010-07|title=Acute myeloid leukemia with inv(16) with CBFB–MYH11, 3′CBFB deletion, variant t(9;22) with BCR–ABL1, and del(7)(q22q32) in a pediatric patient: case report and literature review|url=https://doi.org/10.1016/j.cancergencyto.2010.03.001|journal=Cancer Genetics and Cytogenetics|volume=200|issue=1|pages=54–59|doi=10.1016/j.cancergencyto.2010.03.001|issn=0165-4608}}</ref>, but the mechanisms of disease initiation and cooperation remain unclear<ref name=":2" />.
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
+|}<br />
-----
-</blockquote>
 ==Gene Mutations (SNV/INDEL)==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
+''RUNX1'' mutation is common in AML with ''BCR::ABL1'' and occurs in ~40% of cases<ref name=":13" />. Other mutated genes include ''ASXL1, BCOR, IDH1 / IDH2'' and ''SRSF2''; each of these occur in 10 - 15% of cases<ref name=":14">{{Cite journal|last=Konoplev|first=Sergej|last2=Yin|first2=C. Cameron|last3=Kornblau|first3=Steven M.|last4=Kantarjian|first4=Hagop M.|last5=Konopleva|first5=Marina|last6=Andreeff|first6=Michael|last7=Lu|first7=Gary|last8=Zuo|first8=Zhuang|last9=Luthra|first9=Rajyalakshmi|date=2013-01|title=Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22691121|journal=Leukemia & Lymphoma|volume=54|issue=1|pages=138–144|doi=10.3109/10428194.2012.701739|issn=1029-2403|pmc=3925981|pmid=22691121}}</ref><ref name=":15">{{Cite journal|last=Eisfeld|first=A.-K.|last2=Mrózek|first2=K.|last3=Kohlschmidt|first3=J.|last4=Nicolet|first4=D.|last5=Orwick|first5=S.|last6=Walker|first6=C. J.|last7=Kroll|first7=K. W.|last8=Blachly|first8=J. S.|last9=Carroll|first9=A. J.|date=2017-10|title=The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/28321123|journal=Leukemia|volume=31|issue=10|pages=2211–2218|doi=10.1038/leu.2017.86|issn=1476-5551|pmc=5628133|pmid=28321123}}</ref><ref name=":13" />.Coinciding molecular events such as ''NPM1'' mutations have been reported<ref name=":12" />. Mutations of ''FLT3'' or ''DNMT3A'' are not commonly detected<ref name=":13" />.
 {| class="wikitable sortable"
 |-
-!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
+!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
-'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
+Common >20%, Recurrent 5-20% or Rare <5% (Disease)
-!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
-!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
-!'''Clinical Relevance Details/Other Notes'''
+!Clinical Relevance Details/Other Notes
 |-
-|<span class="blue-text">EXAMPLE:</span>''EGFR''
+|''RUNX1''
 <br />
-|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
+|Variable LOF and missense mutations
-|<span class="blue-text">EXAMPLE:</span> Oncogene
+|Tumor Suppressor Gene
-|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
+|Common (BCR-ABL1 AML)
-|<span class="blue-text">EXAMPLE:</span> T
+|D,P
-|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
+|No
-|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
+|AML with ''RUNX1'' mutation is associated with a poorer prognosis<ref name=":6" />. ''RUNX1'' was the most commonly mutated gene, altered in eight of 21 BCR-ABL1 AML cases (38%)<ref name=":13" />.
-|-
+Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />.
-|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
-<br />
-|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
-|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
-|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
-|<span class="blue-text">EXAMPLE:</span> P
-|
-|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
-|-
-|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
-|<span class="blue-text">EXAMPLE:</span> Activating mutations
-|<span class="blue-text">EXAMPLE:</span> Oncogene
-|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
-|<span class="blue-text">EXAMPLE:</span> T
-|
-|
-|-
-|
-|
-|
-|
-|
-|
-|
-|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
-<blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
-Coinciding molecular events such as ''NPM1'' mutations have been reported<ref name=":1" />.
-{| class="wikitable sortable"
 |-
-!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
+|''ASXL1''
+|Variable LOF and missense mutations
+|Tumor Suppressor Gene
+|Recurrent (BCR-ABL1 AML)
+|D,P
+|No
+|Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />.
 |-
-|''NPM1''|| || || ||
+|''BCOR''
-|}
+|Variable LOF and missense mutations
+|Tumor Suppressor Gene
-===Other Mutations===
+|Recurrent (BCR-ABL1 AML)
-{| class="wikitable sortable"
+|D,P
+|No
+|Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />.
 |-
-!Type!!Gene/Region/Other
+|''IDH1 / IDH2''
+|Missense
+|Oncogene
+|Recurrent (BCR-ABL1 AML)
+|D,P
+|No
+|Other mutated genes include ''ASXL1, BCOR, IDH1 / IDH2'' and ''SRSF2''; each of these occur in 10 - 15% of cases<ref name=":14" /><ref name=":15" /><ref name=":13" />.
 |-
-|Concomitant Mutations||
+|''SRSF2''
+|Missense and in frame del
+|Tumor Suppressor Gene
+|Recurrent (BCR-ABL1 AML)
+|D,P
+|No
+|Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />.
 |-
-|Secondary Mutations||
+|''NPM1''
-|-
+|Variable LOF
-|Mutually Exclusive||
+|Tumor Suppressor Gene and Oncogene
-|}
+|Rare (BCR-ABL1 AML)
+|D,P
-<blockquote class="blockedit">
+|No
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
+|Philadelphia-positive subclones can emerge in ''NPM1''-mutated AML at diagnosis or during follow-up, and may cooperate with the ''NPM1'' mutation like other class I mutations, such as ''FLT3-''ITD or ''MLL-''PTD<ref name=":12" />.
-----
+|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
-</blockquote>
 ==Epigenomic Alterations==
@@ Line 313: / Line 236: @@
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
+The ''BCR'' gene product has serine/threonine kinase activity and is a GTPase-activating protein for p21rac<ref name=":7">{{Cite journal|last=Maru|first=Y.|last2=Witte|first2=O. N.|date=1991|title=The BCR gene encodes a novel serine/threonine kinase activity within a single exon|url=https://www.ncbi.nlm.nih.gov/pubmed/1657398|journal=Cell|volume=67|issue=3|pages=459–468|doi=10.1016/0092-8674(91)90521-y|issn=0092-8674|pmid=1657398}}</ref>. The ''ABL1'' gene is a proto-oncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of this protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene<ref name=":8">{{Cite journal|last=Wang|first=Jean Y. J.|date=2014|title=The capable ABL: what is its biological function?|url=https://www.ncbi.nlm.nih.gov/pubmed/24421390|journal=Molecular and Cellular Biology|volume=34|issue=7|pages=1188–1197|doi=10.1128/MCB.01454-13|issn=1098-5549|pmc=3993570|pmid=24421390}}</ref>. The t(9,22)(q34;q11) leads to the formation of a Philadelphia chromosome and generates an active chimeric BCR-ABL1 tyrosine kinase. The fusion gene is created by juxtaposing the ''ABL1'' gene on chromosome 9 (region q34) to a part of ''BCR'' (breakpoint cluster region) gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome, 22q-), the oncogenic BCR-ABL1 being found on the shorter derivative 22 chromosome<ref name=":9">{{Cite journal|last=Kurzrock|first=Razelle|last2=Kantarjian|first2=Hagop M.|last3=Druker|first3=Brian J.|last4=Talpaz|first4=Moshe|date=2003|title=Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics|url=https://www.ncbi.nlm.nih.gov/pubmed/12755554|journal=Annals of Internal Medicine|volume=138|issue=10|pages=819–830|doi=10.7326/0003-4819-138-10-200305200-00010|issn=1539-3704|pmid=12755554}}</ref><ref name=":10">{{Cite journal|last=Melo|first=J. V.|date=1996|title=The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype|url=https://www.ncbi.nlm.nih.gov/pubmed/8839828|journal=Blood|volume=88|issue=7|pages=2375–2384|issn=0006-4971|pmid=8839828}}</ref>. This gene encodes for a BCR-ABL1 fusion protein, a tyrosine kinase. Tyrosine kinase activities are typically regulated in an auto-inhibitory manner, but the BCR-ABL1 fusion gene codes for a protein that is continuously activated, causing unregulated cell division. This is a result of the replacement of the myristoylated cap region which causes a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein<ref name=":11">{{Cite journal|last=Nagar|first=Bhushan|last2=Hantschel|first2=Oliver|last3=Young|first3=Matthew A.|last4=Scheffzek|first4=Klaus|last5=Veach|first5=Darren|last6=Bornmann|first6=William|last7=Clarkson|first7=Bayard|last8=Superti-Furga|first8=Giulio|last9=Kuriyan|first9=John|date=2003|title=Structural basis for the autoinhibition of c-Abl tyrosine kinase|url=https://www.ncbi.nlm.nih.gov/pubmed/12654251|journal=Cell|volume=112|issue=6|pages=859–871|doi=10.1016/s0092-8674(03)00194-6|issn=0092-8674|pmid=12654251}}</ref>. The enzyme is responsible for the uncontrolled growth of leukemic cells which survive better than normal blood cells. As a result of BCR/ABL1 variable splicing (fusion RNA and hybrid proteins), two transcripts p190 and p210 are found for BCR-ABL1 positive AML.
 {| class="wikitable sortable"
 |-
 !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 |-
-|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
+|''BCR'' and ''ABL1''; Activating mutations
-|<span class="blue-text">EXAMPLE:</span> MAPK signaling
+|Ras/MAPK, PI3K/AKT, JAK/STAT and NF-kappaB pathways
-|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
+|The BCR-ABL fusion protein is an constitutively active tyrosine kinase that triggers multiple pathways,  promoting unchecked cell proliferation and survival.
-|-
-|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
-|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
-|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
-|-
-|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
-|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
-|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
-|-
-|
-|
-|
 |}
-<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
+<br />
-The ''BCR'' gene product has serine/threonine kinase activity and is a GTPase-activating protein for p21rac<ref>{{Cite journal|last=Maru|first=Y.|last2=Witte|first2=O. N.|date=1991|title=The BCR gene encodes a novel serine/threonine kinase activity within a single exon|url=https://www.ncbi.nlm.nih.gov/pubmed/1657398|journal=Cell|volume=67|issue=3|pages=459–468|doi=10.1016/0092-8674(91)90521-y|issn=0092-8674|pmid=1657398}}</ref>. The ''ABL1'' gene is a proto-oncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of this protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene<ref>{{Cite journal|last=Wang|first=Jean Y. J.|date=2014|title=The capable ABL: what is its biological function?|url=https://www.ncbi.nlm.nih.gov/pubmed/24421390|journal=Molecular and Cellular Biology|volume=34|issue=7|pages=1188–1197|doi=10.1128/MCB.01454-13|issn=1098-5549|pmc=3993570|pmid=24421390}}</ref>. The t(9,22)(q34;q11) leads to the formation of a Philadelphia chromosome and generates an active chimeric BCR-ABL1 tyrosine kinase. The fusion gene is created by juxtaposing the ''ABL1'' gene on chromosome 9 (region q34) to a part of ''BCR'' (breakpoint cluster region) gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome, 22q-), the oncogenic BCR-ABL1 being found on the shorter derivative 22 chromosome<ref>{{Cite journal|last=Kurzrock|first=Razelle|last2=Kantarjian|first2=Hagop M.|last3=Druker|first3=Brian J.|last4=Talpaz|first4=Moshe|date=2003|title=Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics|url=https://www.ncbi.nlm.nih.gov/pubmed/12755554|journal=Annals of Internal Medicine|volume=138|issue=10|pages=819–830|doi=10.7326/0003-4819-138-10-200305200-00010|issn=1539-3704|pmid=12755554}}</ref><ref>{{Cite journal|last=Melo|first=J. V.|date=1996|title=The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype|url=https://www.ncbi.nlm.nih.gov/pubmed/8839828|journal=Blood|volume=88|issue=7|pages=2375–2384|issn=0006-4971|pmid=8839828}}</ref>. This gene encodes for a BCR-ABL1 fusion protein, a tyrosine kinase. Tyrosine kinase activities are typically regulated in an auto-inhibitory manner, but the BCR-ABL1 fusion gene codes for a protein that is continuously activated, causing unregulated cell division. This is a result of the replacement of the myristoylated cap region which causes a conformational change rendering the kinase domain inactive, with a truncated portion of the BCR protein<ref>{{Cite journal|last=Nagar|first=Bhushan|last2=Hantschel|first2=Oliver|last3=Young|first3=Matthew A.|last4=Scheffzek|first4=Klaus|last5=Veach|first5=Darren|last6=Bornmann|first6=William|last7=Clarkson|first7=Bayard|last8=Superti-Furga|first8=Giulio|last9=Kuriyan|first9=John|date=2003|title=Structural basis for the autoinhibition of c-Abl tyrosine kinase|url=https://www.ncbi.nlm.nih.gov/pubmed/12654251|journal=Cell|volume=112|issue=6|pages=859–871|doi=10.1016/s0092-8674(03)00194-6|issn=0092-8674|pmid=12654251}}</ref>. The enzyme is responsible for the uncontrolled growth of leukemic cells which survive better than normal blood cells. As a result of BCR/ABL1 variable splicing (fusion RNA and hybrid proteins), two transcripts p190 and p210 are found for BCR-ABL1 positive AML.
-[[File:BCR-ABL1 translocation image.jpg|Figure 1. Philadelphia chromosome. A piece of chromosome 9 and a piece of chrosomome 22 break off and trade places. The BCR-ABL1 gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called Philadelphia chromosome. Image from National Cancer Institute website https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bcr-abl-fusion-gene|frame|center]]
-<blockquote class="blockedit">
+[[File:BCR-ABL1 translocation image.jpg|Figure 1. Philadelphia chromosome. A piece of chromosome 9 and a piece of chrosomome 22 break off and trade places. The BCR-ABL1 gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called Philadelphia chromosome. Image from National Cancer Institute website https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bcr-abl-fusion-gene|frame|alt=|none]][[File:Screenshot 2025-05-11 181714.png|thumb|Figure 2. Signal transduction pathway of the BCR-ABL fusion gene|alt=|none]]
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
 ==Genetic Diagnostic Testing Methods==
-Bone marrow with myeloid blasts >20% combined with detection of t(9,22) by karytoype analysis or BCR-ABL1 using FISH or reverse transcriptase-quantitative PCR (RT-qPCR)<ref name=":2" />.  A graphic of the clinical path for the differential diagnosis of BCR-ABL1 positive acute myeloid leukemia and chronic myeloid leukemia-myeloid blast crisis (CML-MBC) is presented<ref name=":2" />.
+Bone marrow with myeloid blasts >20% combined with detection of t(9,22) by karyotype analysis or BCR-ABL1 using FISH or reverse transcriptase-quantitative PCR (RT-qPCR) and RNA or DNA seq<ref name=":2" />.  A graphic of the clinical path for the differential diagnosis of BCR-ABL1 positive acute myeloid leukemia and chronic myeloid leukemia-myeloid blast crisis (CML-MBC) is presented<ref name=":2" />.
 ==Familial Forms==
@@ Line 366: / Line 270: @@
 ==References==
-(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
+<references />
 <br />

HAEM5:Acute myeloid leukaemia with BCR::ABL1 fusion: Difference between revisions

Latest revision as of 12:06, 3 July 2025

Primary Author(s)*

WHO Classification of Disease

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDEL)

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

Additional Information

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References

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