t(9;22)(q34;q11) BCR/ABL1 in AML

1997-09-01   Jean-Loup Huret  

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Clinics and Pathology

Disease

AML

Phenotype stem cell origin

mostly M1 or M2 AML

Epidemiology

3% of AML; 1% in childhood AML

Prognosis

is very poor

Genes Involved and Proteins

Gene name
ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)
Location
9q34.12
Dna rna description
alternate splicing (1a and 1b) in 5
Protein description
giving rise to 2 proteins of 145 kDa; contains SH (SRChomology) domains; N-term SH3 and SH2 - SH1 (tyrosine kinase) - DNA bindingmotif - actin binding domain C-term; widely expressed; localisation ismainly nuclear; inhibits cell growth
Gene name
BCR (Breakpoint cluster region)
Location
22q11.23
Dna rna description
various splicings
Protein description
main form: 160 KDa; N-term Serine-Treonine kinase
Protein description
domain, SH2 binding, and C-term domain which functions as a GTPase
Protein description
activating protein for p21rac; widely expressed; cytoplasmic localisation;
Protein description
protein kinase; probable role in signal transduction

Result of the Chromosomal Anomaly

Description

  • the crucial event lies on der(22), id est 5 BCR/3 ABLexon of BCR binds to SH2, hidding SH3 which, as a consequence, cannot bebound to 3BP1; thereof, SH1 is activatedtwo alternative exons 1b and 1a, sometimes 5 of 1b, or 3 of 1a, butalways 5 of exon 2; - breakpoint in BCR is either (as in ALL cases): 1- inthe same region as in CML, called M-bcr (for major breakpoint clusterregion), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5of M-bcr; most breakpoints being either between b2 and b3, or between b3and b4; transcript is 8.5 kb long; this results in a 210 KDa chimericprotein (P210), with the first 902 or 927 amino acids from BCR; 2- in a 35kb region between exons 1 and 2, called m-bcr (minor breakpoint clusterregion), -> 7 kb mRNA, resulting in a 190 KDa protein (P190), with the 427N-terminal amino acids from BCR

    • Transcript

    7 or 8.5 kb

    Description

    190 or 210 kDa (see above); BCR/ABL has a cytoplasmic

    Description

    localization, in contrast with ABL, mostly nuclear; this may have a

    Description

    carcinogenetic role. The hybrid protein has an increased protein kinase

    Description

    activity compared to ABL: 3BP1 (binding protein) binds normal ABL on SH3

    Description

    domain, which prevents SH1 activation; with BCR/ABL, the first (N-terminal)

    Oncogenesis

    1- proliferation is induced: there is activation by BCR/ABL ofRas signal transduction pathway via its linkage to son-of-sevenless (SOS),a Ras activator; PI3-K (phosphatidyl inositol 3 kinase) pathway is alsoactivated; MYC as well; 2- BCR/ABL inhibits apoptosis; 3- BCR/ABL provokescell adhesive abnormalities: impaired adherence to bone marrow stromacells, which allows unregulated proliferation of leukaemic progenitors

    Highly cited references

    Pubmed IDYearTitleCitations
    349977662022Assessment of quantitative polymerase chain reaction for BCR-ABL1 transcripts in chronic myeloid leukaemia: Are improved outcomes in patients with e14a2 transcripts an artefact of technology?2
    356160062022Pharmacokinetics of asciminib in the presence of CYP3A or P-gp inhibitors, CYP3A inducers, and acid-reducing agents.1
    353570362022Treatment-free remission in patients with chronic myeloid leukemia following the discontinuation of tyrosine kinase inhibitors.1
    347478762022Tyrosine kinase domain mutations in chronic myelogenous leukemia patients: A single center experience.1
    355433092022Saudi Arabian CML patient with a novel four-way translocation at t(9;22;5;2)(q34;q11.2;p13;q44).1
    359928472022Polo-like kinase-1, Aurora kinase A and WEE1 kinase are promising druggable targets in CML cells displaying BCR::ABL1-independent resistance to tyrosine kinase inhibitors.0
    359915502022A Systematic Review of Reproductive Counseling in Cases of Parental Constitutional Reciprocal Translocation (9;22) Mimicking BCR-ABL1.0
    359635222022Fusion Gene Detection and Quantification by Asymmetric Capture Sequencing (aCAP-Seq).0
    359323962022Defining Higher-Risk Chronic Myeloid Leukemia: Risk Scores, Genomic Landscape, and Prognostication.0
    359163332022HHV8-negative primary effusion-based large B-cell lymphoma in a patient with chronic myeloid leukemia, BCR::ABL1-positive under dasatinib treatment: Report of a new case and literature review.0
    359081052022Droplet digital PCR for the detection of second-generation tyrosine kinase inhibitor-resistant BCR::ABL1 kinase domain mutations in chronic myeloid leukemia.0
    358784532022Patient-specific molecular response dynamics can predict the possibility of relapse during the second treatment-free remission attempt in chronic myelogenous leukemia.0
    358423552022Efficacy and Safety of Generic Dasatinib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: A Multicenter Prospective Study in China.0
    357948482022BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia.0
    356992772022Initial Rate of BCR::ABL1 Decline for Response Prediction in Chronic Myeloid Leukemia0
    356209652022Highly sensitive droplet digital polymerase chain reaction for BCR::ABL1 messenger RNA identifies patients with chronic myeloid leukaemia with a low probability of achieving treatment-free remission.0
    356204432022Predictive Factors for Molecular Response in Chronic Myeloid Leukemia: Reduction Ratio and Halving Time of BCR::ABL1 IS Transcript Levels0
    355990192022Application of precision medicine in clinical routine in haematology-Challenges and opportunities.0
    355624922022Subclonal acquisition of a BCR::ABL1 fusion in a chronic myelomonocytic leukemia.0
    354840802022Clinico-hematological and Outcome Profile of Pediatric B-other-ALL and BCR::ABL1-like pre-B-ALL: An Integrated Genomic Study From North India.0
    354038162022Discontinuation of tyrosine kinase inhibitors in pediatric chronic myeloid leukemia.0
    353781182022Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.0
    352901572022Significance of RUNX1 mutation in BCR-ABL1 positive acute myeloid leukemia - a diagnostic dilemma in a young woman with persistent bleeding.0
    360112852022Commonly Assessed Markers in Childhood BCP-ALL Diagnostic Panels and Their Association with Genetic Aberrations and Outcome Prediction.0
    358929002022Novel Dicarboximide BK124.1 Breaks Multidrug Resistance and Shows Anticancer Efficacy in Chronic Myeloid Leukemia Preclinical Models and Patients' CD34+/CD38- Leukemia Stem Cells.0
    358698052022Comparison of molecular responses and outcomes between BCR::ABL1 e14a2 and e13a2 transcripts in chronic myeloid leukemia.0
    358163602022Inflammation accelerates BCR-ABL1+ B-ALL development through upregulation of AID.0
    358096442022Allosteric Enhancement of the BCR-Abl1 Kinase Inhibition Activity of Nilotinib by Co-Binding of Asciminib.0
    356764532022Impact of BCR::ABL1 transcript type on RT-qPCR amplification performance and molecular response to therapy.0
    356410282022Dasatinib suppresses atherosclerotic lesions by suppressing cholesterol uptake in a mouse model of hypercholesterolemia.0
    356143192022Standardization of molecular monitoring of CML: results and recommendations from the European treatment and outcome study.0
    355978062022Inability to phosphorylate Y88 of p27Kip1 enforces reduced p27 protein levels and accelerates leukemia progression.0
    353895072022Erythrophagocytosis by blast cells in B-lymphoblastic leukaemia with BCR-ABL1.0
    358478412022The Molecular Role of HIF1α Is Elucidated in Chronic Myeloid Leukemia.0
    357825812022AML with BCR-ABL1 Fusion treated with Imatinib, a Hypomethylating Agent and Venetoclax.0
    357732742022Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia.0
    357566862022Successful Preservation of Native BCR::ABL1 in Chronic Myeloid Leukemia Primary Leukocytes Reveals a Reduced Kinase Activity.0
    357352032022Immunophenotypic characteristics of ZNF384 rearrangement compared with BCR-ABL1, KMT2A rearrangement, and other adult B-cell precursor acute lymphoblastic leukemia.0
    356755142022The Impact of T cell Immunity on Chemotherapy Response in Childhood Acute Lymphoblastic Leukemia.0
    354911242022TM5614, an Inhibitor of Plasminogen Activator Inhibitor-1, Exerts an Antitumor Effect on Chronic Myeloid Leukemia.0
    353441152022Identification and validation of suitable housekeeping genes for gene expression studies in BCR-ABL1 positive B-lineage acute lymphoblastic leukemia.0
    352986132022The differential role of the lipid raft-associated protein flotillin 2 for progression of myeloid leukemia.0
    351717272022MUC4 expression by immunohistochemistry is a specific marker for BCR-ABL1+ and BCR-ABL1-like B-lymphoblastic leukemia.0
    351420612022Identification of peripheral blood CD26+ leukemic stem cells has a potential role in the rapid diagnosis of chronic myeloid leukemia.0
    350835262022Multiple erythrophagocytosis by erythroid blasts in acute myeloid leukemia with BCR-ABL1.0
    350603182022P-Loop mutations-Negative prognosticators in tyrosine kinase inhibitors resistant chronic myeloid leukemia patients.0
    360324222022High incidence of minor and micro breakpoints in Chronic Myeloid Leukaemia with additional cytogenetic abnormalities at diagnosis - the Western Australian series.0
    360171022022Variables associated with pulmonary hypertension screened by echocardiography in chronic myeloid leukemia patients on dasatinib therapy.0
    360153022022Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia.0
    359993582022Creation of Philadelphia chromosome by CRISPR/Cas9-mediated double cleavages on BCR and ABL1 genes as a model for initial event in leukemogenesis.0
    359824832022Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial.0
    359398872022Efficacy of ruxolitinib in acute lymphoblastic leukemia: A systematic review.0
    359389512022JAK2 V617f in chronic myeloid leukemia: driving force or passive bystander?0
    359335232022Minimal residual disease in BCR::ABL1-positive acute lymphoblastic leukemia: different significance in typical ALL and in CML-like disease.0
    359209652022Management of Chronic Myeloid Leukemia in Children and Young Adults.0
    359027312022ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia.0
    357518592022Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring.0
    354293302022Secondary chronic myeloid leukemia in a patient with CALR and ASXL1-mutated primary myelofibrosis.0
    357411152022Digital Droplet PCR in Hematologic Malignancies: A New Useful Molecular Tool.0
    356826272022Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors.0
    356651312022Primary isolated central nervous system acute lymphoblastic leukemia with BCR-ABL1 rearrangement: A case report.0
    356647812022Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma.0
    356472822022Development of a First-in-Class Small-Molecule Inhibitor of the C-Terminal Hsp90 Dimerization.0
    355715282022Diagnosis and Management of Atypical Chronic Myeloid Leukemia with a t(2;13)(q33;q12) Translocation.0
    355700712022Long-term safety review of tyrosine kinase inhibitors in chronic myeloid leukemia - What to look for when treatment-free remission is not an option.0
    355514632022BCR::ABL1 tyrosine kinase inhibitors hamper the therapeutic efficacy of blinatumomab in vitro.0
    355446702022An evaluation of ponatinib as a therapy in adult patients with resistant/intolerant chronic-phase chronic myeloid leukemia.0
    355272442022Influence of cytochrome P450 and glutathione S transferase polymorphisms on response to nilotinib therapy among chronic myeloidleukemia patients from Pakistan.0
    355240232022Introduction of the T315I gatekeeper mutation of BCR/ABL1 into a Philadelphia chromosome-positive lymphoid leukemia cell line using the CRISPR/Cas9 system.0
    354124042022Ponatinib for the treatment of adult patients with resistant or intolerant Chronic-Phase Chronic Myeloid Leukemia.0
    349034892022State-of-the-Art Review on Myelofibrosis Therapies.0
    359675712022Discontinuation of tyrosine kinase inhibitors based on BCR-ABL1 monitoring by digital droplet PCR in pediatric chronic myeloid leukemia.0
    359497662022Trametinib: Could It Be a Promising Drug to Treat Atypical Chronic Myeloid Leukemia?0
    359064702022Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA.0
    359030382022Highly precise breakpoint detection of chromosome balanced translocation in chronic myelogenous leukaemia: Case series.0
    358954642022Két myeloproliferativ betegség egy betegben - klónok együttélése és vetélkedése.0
    358870632022Ketoconazole Reverses Imatinib Resistance in Human Chronic Myelogenous Leukemia K562 Cells.0
    358843632022Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia.0
    358603452022Migrating to Long-Read Sequencing for Clinical Routine BCR-ABL1 TKI Resistance Mutation Screening.0
    358342222022Treatment of Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia-From Intensive Chemotherapy Combinations to Chemotherapy-Free Regimens: A Review.0
    358332972022RHOA regulated IGFBP2 promotes invasion and drives progression of BCR-ABL1 chronic myeloid leukemia.0
    357940902022Chronic phase CML with sole P190 (e1a2) BCR::ABL1: long-term outcome among ten consecutive cases.0
    357760722022Exposure-Efficacy Analysis of Asciminib in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase.0
    357255932022[French Chronic Myeloid Leukemia Intergroup 2022 recommendations for managing the risk of cardiovascular events on ponatinib in chronic myeloid leukemia].0
    353610362022Intracranial hypertension associated with BCR-ABL1 tyrosine kinase inhibitors in chronic myeloid leukemia.0
    351657772022A case report of BCR-ABL1 rearrangement in de novo adult T-cell lymphoblastic leukemia/lymphoma with normal karyotype.0
    354556862022The Use of Allogeneic Hematopoietic Stem Cell Transplantation in Primary Myelofibrosis.0
    353584412022Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial.0
    351418592022Discontinuation of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia: a Review of the Biological Factors Associated with Treatment-Free Remission.0
    351127162022BCR::ABL1 transcripts and clinical outcome - interrogating the technique.0
    345855202022Quantification of atypical BCR-ABL1 fusion transcripts in patients with chronic myeloid leukemia: Which approach for harmonization?0
    335263732022Precursor B-lineage acute lymphoblastic leukemia patients with aberrant natural killer cell and T cell - lineage antigen expression: experience from a tertiary cancer care center.0
    357647732022Population Pharmacokinetics of Asciminib in Tyrosine Kinase Inhibitor-Treated Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic and Acute Phases.0
    357298502022Asciminib for chronic myeloid leukaemia: Next questions.0
    356866572022BCR/ABL1ΔE7-8-9 isoform contributes to tyrosine kinase inhibitor resistance in chronic myeloid leukemia.0
    356502772022Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions.0
    356093362022The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved Drug.0
    355833862022An evaluation of asciminib for patients with chronic myeloid leukemia previously treated with ≥2 tyrosine kinase inhibitors.0
    354681802022Asciminib: a new therapeutic option in chronic-phase CML with treatment failure.0
    354118072022Burden of tyrosine kinase inhibitor failure in Chinese chronic myeloid leukemia patients: a systematic literature review.0

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    90503731997The function of BCR/ABL and related proto-oncogenes.Gotoh A et al
    20506001991Molecular insights into the Philadelphia translocation.Heisterkamp N et al
    19317061991The molecular pathology of chronic myelogenous leukaemia.Kurzrock R et al

    Summary

    Note

    Although the same hybrid genes issued from ABL and BCRare the hallmark of the t(9;22) translocation, this translocationmay be seen in the following diseases: CML, AML, and ALL, and willtherefore be described in the 3 different situations: t(9;22)(q34;q11) inCML, t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in AMLt(9;22)(q34;q11) in AML is herein described
    Atlas Image
    t(9;22)(q34;q11) G- banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (3 top) and Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services (2 bottom); R-banding (right) top: Editor; 2 others Courtesy Jean-Luc Lai and Alain Vanderhaegen); diagram and breakpoints (Editor).

    Citation

    Jean-Loup Huret

    t(9;22)(q34;q11) BCR/ABL1 in AML

    Atlas Genet Cytogenet Oncol Haematol. 1997-09-01

    Online version: http://atlasgeneticsoncology.org/haematological/1023/tumors-explorer/cancer-prone-explorer/gene-explorer/