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==Primary Author(s)*==

Kay Weng Choy MBBS, Monash Medical Centre

__TOC__

==Cancer Category/Type==

Acute Myeloid Leukemia (AML)

==Cancer Sub-Classification / Subtype==

AML with BCR-ABL1

==Definition / Description of Disease==

AML with BCR-ABL1 is a rare subtype of AML that is now included as a provisional entity under the heading of “AML with recurrent genetic abnormalities” in the 2016 revised World Health Organization (WHO) classification of myeloid malignancies<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>. It must be distinguished from myeloid blast crisis of chronic myeloid leukemia (CML-MBC) and mixed phenotype acute leukemia (MPAL) with BCR-ABL1, which are separate entities in the WHO classification. The t(9:22)(q34.1;q11.2) results in the formation of the Philadelphia chromosome and the chimeric BCR-ABL1 fusion gene. It is worth noting that the fusion gene is the cytogenetic hallmark of chronic myelogenous leukemia (CML) and is frequently found in high-risk acute lymphoblastic leukemia (ALL).

Table [adapted from <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>] - Differentiating CML-MBC from AML with BCR-ABL1
{| class="wikitable sortable"
|-
!CML-MBC!!AML with BCR-ABL1
|-
|Previous blood disorder, idiopathic leucocytosis||No previous blood disorder
|-
|Splenomegaly||No splenomegaly
|-
|Basophilia (≥2%)||No basophilia
|-
|~100% marrow cellularity||<100% marrow cellularity (median 80%)
|-
|Typical AML blast crisis phenotype||Aberrant CD19, CD7 and TdT more common
|-
|Ph+ in ~100% of cells||Ph+ in <100% of cells
|-
|P210 transcript in >99% of cases||p190 and p210 detected in nearly equal distribution
|-
| ||Loss of ''IKZF1'' and ''CDKN2A'' and cryptic deletions within ''IGH'' and ''TCR'' genes
|}

Most cases which carry the BCR-ABL1 fusion have been described as ''de novo'' AML; there are only a few cases described where acquisition of the Philadelphia chromosome upon disease relapse or transformation of antecedent myelodysplastic syndrome into AML occurred<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>. Based on one model of leukemogenesis in which two driver mutations are required (a class-II mutation, conferring inhibition of differentiation and apoptosis, and a class-I mutation conferring a proliferative advantage), BCR-ABL1 is likely to represent a class-I mutation<ref name=":2" />.

==Synonyms / Terminology==

Not applicable

==Epidemiology / Prevalence==

It is reported that up to 3% of all AML carry BCR-ABL1 fusions. The overall incidence is mainly estimated from larger case series without any standardized definition<ref name=":2" />.

==Clinical Features==

Little is known about the characteristics clinical features of BCR-ABL1 positive AML. In contrast to CML, BCR-ABL1 positive AML has no antecedent hematologic disease/abnormality and no splenomegaly. Unexplained leucocytosis and/or splenomegaly point towards the diagnosis of CML myeloid blast crisis (CML-MBC) than AML<ref name=":2" />. Soupir et al. reported 16 cases of BCR-ABL1 positive AML, noting there was some overlap phenotypically and morphologically with CML myeloid blast crisis, but BCR-ABL1 positive AML cases presented less often with splenomegaly, lacked basophilia and had lower bone marrow cellularity<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|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://www.ncbi.nlm.nih.gov/pubmed/17369142|journal=American Journal of Clinical Pathology|volume=127|issue=4|pages=642–650|doi=10.1309/B4NVER1AJJ84CTUU|issn=0002-9173|pmid=17369142}}</ref>.

==Sites of Involvement==

Bone marrow

==Morphologic Features==

BCR-ABL1 positive AML features include myeloid blasts >20% found in the bone marrow, below a blast count of 20% the WHO classification currently describes diagnosis of BCR-ABL1 AML as controversial. It is helpful to note several features that may help in the differential diagnosis of BCR-ABL1 positive AML: basophilia (>2% in white blood cells) strongly diminishes the probability of ''de novo'' AML (most cases of BCR-ABL1 positive AML are ''de novo'' AML); prior signs of myelodysplastic syndrome (MDS) in peripheral blood or bone marrow may support the diagnosis of secondary AML<ref name=":2" />.

==Immunophenotype==

Co-expression of lymphoid markers have been reported in BCR-ABL1 positive cases. Atfy et al., reported an aberrant lymphoid co-expression in seven of nine BCR-ABL1 positive AML cases<ref>{{Cite journal|last=Atfy|first=Maha|last2=Al Azizi|first2=Nashwa M. A.|last3=Elnaggar|first3=Amina M.|date=2011|title=Incidence of Philadelphia-chromosome in acute myelogenous leukemia and biphenotypic acute leukemia patients: And its role in their outcome|url=https://www.ncbi.nlm.nih.gov/pubmed/21612824|journal=Leukemia Research|volume=35|issue=10|pages=1339–1344|doi=10.1016/j.leukres.2011.04.011|issn=1873-5835|pmid=21612824}}</ref>. Soupir et al. reported that there was no significant difference in the blast immunophenotype by flow cytometry between the BCR-ABL positive AML and CML-MBC cases. In nearly all cases in both groups, the blasts expressed CD13, CD33, and CD34<ref name=":3" />. However, compared to CML-MBC, aberrant CD19, CD7 and TdT have been found to be more common in BCR-ABL1 positive AML<ref name=":1" />.

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||Myeloid antigens (CD13 and CD33), CD34
|-
|Positive (subset)||CD19, CD7, TdT
|-
|Negative (universal)||
|-
|Negative (subset)||
|}

==Chromosomal Rearrangements (Gene Fusions)==

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" />. 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" />.

{| class="wikitable sortable"
|-
!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
|}

==Characteristic Chromosomal Aberrations / Patterns==

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).

==Genomic Gain/Loss/LOH==

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" />.

{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|7||Loss||chr7
|-
|8||Gain||chr8
|}

==Gene Mutations (SNV/INDEL)==

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)
|-
|''NPM1''|| || || ||
|}

===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||
|-
|Secondary Mutations||
|-
|Mutually Exclusive||
|}

==Epigenomics (Methylation)==

Not applicable

==Genes and Main Pathways Involved==

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]]

==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" />.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

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" />.

==Familial Forms==

Not applicable

==Other 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==
<references />

==Notes==
<nowiki>*</nowiki>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 CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

[[Category:Translocation]]
[[Category:Translocation Chromosome 9]]
[[Category:Translocation Chromosome 22]]
[[Category:Structural Chromosome Abnormalities]]
[[Category:Structural Chromosome Abnormalities in AML]]
[[Category:Structural Abnormalities Chromosome 9]]
[[Category:Structural Abnormalities Chromosome 22]]
[[Category:Fusion Genes in AML]]
[[Category:Fusion Genes A]]
[[Category:Fusion Genes B]]
[[Category:Recently Added Pages]]

HAEM4Backup:Acute Myeloid Leukemia (AML) with BCR-ABL1 - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== Kay Weng Choy MBBS, Monash Medical Centre __TOC__ ==Cancer Category/Type== Acute Myeloid Leukemia (AML) ==Cancer Sub-Classification / Subtype== AM..."

Bailey.Glen: Created page with "==Primary Author(s)*== Kay Weng Choy MBBS, Monash Medical Centre TOC ==Cancer Category/Type== Acute Myeloid Leukemia (AML) ==Cancer Sub-Classification / Subtype== AM..."