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

|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 chronic myeloid leukaemia (CML) before or at diagnosis or after therapy.

|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.

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>{{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>.

|''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 ~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. 

 

 

 

 

|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>.

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>.  

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" />.

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>.

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>.

|}<center>

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>.

|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

|Unknown

|D,P

|No

|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 />

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=":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). 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.''

|inv(16)(p13.1q22) or t(16;16)(p13.1;q22)

|CBFB::MYH11 fusion

|

|t(8;21)(q22;q22.1)

|RUNX1- RUNX1T1

|-

|AML-myelodysplasia-related (AML-MR) cytogenetic aberrations:

 

 

 

 

• Isochromosome 17q, del(17p)  

|}<br />

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.

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.