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

|acute myeloid leukaemia with t(9;22)(q34;q11.2)

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|Common ~90-95% (CML)<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>; Rare ~0.5 - 3% (AML)<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>.<!-- 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>.

|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>. 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>.  

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" />.

There is a single case report of a patient 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>.  

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!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'''

!'''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'''

|No

• 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>

In AML, BCR-ABL appears to interact with specific aberrations like inv(16) and myelodysplasia-related cytogenetic changes, but the mechanisms of disease initiation and cooperation remain unclear<ref name=":2" />.

Coinciding molecular events such as ''NPM1'' mutations have been reported<ref name=":12" />. ''RUNX1'' mutation is common in AML with ''BCR::ABL1'' and occurs in ~40% of cases<ref name=":13" />.

 

Mutations of ''NPM1, FLT3'' or ''DNMT3A'' are not commonly detected<ref name=":13" />. Other mutated genes include ''ASXL1, BCOR, IDH1 / IDH2'' and ''SRSF2''; each of these occur in 10 - 15% of cases<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><ref>{{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" />.

!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'''

|<span class="blue-text">EXAMPLE:</span>''EGFR''

|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations

|<span class="blue-text">EXAMPLE:</span> Oncogene

|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)

|<span class="blue-text">EXAMPLE:</span> T

|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)

|<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).

|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations

|<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

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The ''BCR'' gene product has serine/threonine kinase activity and is a GTPase-activating protein for p21rac<ref name=":7" />. 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" />. 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" /><ref name=":10" />. 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" />. 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.

|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations

|<span class="blue-text">EXAMPLE:</span> MAPK signaling

|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation

|-

|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations

|<span class="blue-text">EXAMPLE:</span> Unregulated cell division

|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations

<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>

 

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.

 

<center><span style="color:Maroon">'''End of V4 Section'''</span>

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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)<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" />.