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

1997-09-01   Jean-Loup Huret  , Jean-Loup Huret  

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

Clinics and Pathology

Disease

ALL

Phenotype stem cell origin

L1 or L2 ALL; most often with B-cell phenotype, rare T-cell cases; heterogeneity of lineage involvement: may either be a multipotent stem cell, or a lymphoid-committed progenitor.

Epidemiology

20% of adult ALL, 2-5% of children ALL

Clinics

frequent CNS involvement, even at diagnosis; blood data: high WBC (50-150 X 109/l).

Cytology

CD10+ in most cases, sometimes CD19+ CD10-

Treatment

BMT is indicated

Prognosis

is very poor, especially in lymphoid-committed progenitor cases; the breakpiont in M-bcr or in m-bcr (see below) does not seem to have impact on prognosis.

Cytogenetics

Cytogenetics morphological

the chromosomal anomaly disappear during remission, in contrast with BC-CML cases when treated with conventional therapies.

Cytogenetics molecular

is useful to uncover a masked Philadelphiachromosome, where chromosomes 9 and 22 all appear to be normal, but wherecryptic insertion of 3 ABL within a chromosome 22 can be demonstrated

Additional anomalies

found in 50 to 80% of cases: +der(22), -7, del(7q)most often, +8, but not an i(17q), in contrast with CML and AML cases;complex karyotypes, often hyperploid, are frequent

Variants

t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variablechromosome, may be found, as in CML

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 domain,

    Description

    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
    350571082022BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia.188
    188271852009Molecular biology of bcr-abl1-positive chronic myeloid leukemia.137
    358843632022Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia.123
    288041222018SHP2 is required for BCR-ABL1-induced hematologic neoplasia.99
    373371052023Transcriptomic classes of BCR-ABL1 lymphoblastic leukemia.91
    385509482023Targeting BCR-ABL1-positive leukaemias: a review article.88
    386532452024Integrated drug profiling and CRISPR screening identify BCR::ABL1-independent vulnerabilities in chronic myeloid leukemia.83
    376291882023Diagnosis- and Prognosis-Related Gene Alterations in BCR::ABL1-Negative Myeloproliferative Neoplasms.80
    390989222024BCR::ABL1 Proteolysis-targeting chimeras (PROTACs): The new frontier in the treatment of Ph(+) leukemias?75
    384574942024ERG and c-MYC regulate a critical gene network in BCR::ABL1-driven B cell acute lymphoblastic leukemia.73
    383972212024Frequencies of BCR::ABL1 Transcripts in Patients with Chronic Myeloid Leukemia: A Meta-Analysis.67
    373732662023Molecular BCR::ABL1 Quantification and ABL1 Mutation Detection as Essential Tools for the Clinical Management of Chronic Myeloid Leukemia Patients: Results from a Brazilian Single-Center Study.66
    273663122016New Developments in Chronic Myeloid Leukemia: Implications for Therapy.65
    331941572020NPM1 Mutated, BCR-ABL1 Positive Myeloid Neoplasms: Review of the Literature.64
    342763652021Impact of the Breakpoint Region on the Leukemogenic Potential and the TKI Responsiveness of Atypical BCR-ABL1 Transcripts.62
    373860792023MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia.61
    382826772023Co-occurrence of JAK2-V617 F mutation and BCR::ABL1 translocation in chronic myeloproliferative neoplasms: a potentially confounding genetic combination.60
    332831682020Digital PCR for BCR-ABL1 Quantification in CML: Current Applications in Clinical Practice.58
    371610702023Mast cell deficiency prevents BCR::ABL1 induced splenomegaly and cytokine elevation in a CML mouse model.58
    321546682020Next-generation sequencing for BCR-ABL1 kinase domain mutations in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A position paper.53
    339490402021RAG enhances BCR-ABL1-positive leukemic cell growth through its endonuclease activity in vitro and in vivo.53
    355514632022BCR::ABL1 tyrosine kinase inhibitors hamper the therapeutic efficacy of blinatumomab in vitro.51
    383869752024Tyrosine kinase inhibitor resistance in de novo BCR::ABL1-positive BCP-ALL beyond kinase domain mutations.51
    396524552025BCR::ABL1-induced mitochondrial morphological alterations as a potential clinical biomarker in chronic myeloid leukemia.51
    312892062020Human BCR/ABL1 induces chronic myeloid leukemia-like disease in zebrafish.49
    262911292015MAPK15 mediates BCR-ABL1-induced autophagy and regulates oncogene-dependent cell proliferation and tumor formation.47
    261790662015BCR/ABL1 and BCR are under the transcriptional control of the MYC oncogene.46
    378755832023Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia.44
    313118092019Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation.42
    394406952024New ABL1 Kinase Domain Mutations in BCR::ABL1-Positive Acute Lymphoblastic Leukemia.42
    349022052022RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia.42
    358163602022Inflammation accelerates BCR-ABL1+ B-ALL development through upregulation of AID.41
    374008422023BCR::ABL1-like acute lymphoblastic leukaemia: a single institution experience on identification of potentially therapeutic targetable cases.41
    315434642019Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants.40
    371650012023Targeting Poly(ADP)ribose polymerase in BCR/ABL1-positive cells.40
    378079802023High BCR::ABL1 Expression Defines CD34+ Cells with Significant Alterations in Signal Transduction, Short-Proliferative Potential and Self-Renewal Ability.39
    385963592024Chronic myeloproliferative neoplasms with concomitant CALR mutation and BCR::ABL1 translocation: diagnostic and therapeutic implications of a rare hybrid disease.38
    212998492011BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance.38
    314569472019BCR-ABL1 Doubling-Times and Halving-Times May Predict CML Response to Tyrosine Kinase Inhibitors.37
    383958952024Pharmacovigilance study of BCR-ABL1 tyrosine kinase inhibitors: a safety analysis of the FDA adverse event reporting system.36
    276117422016Novel BCR-ABL1 fusion and leukemic mutations of SETBP1, PAX5, and TP53 detected by next generation sequencing in chronic myeloid leukemia.36
    285338182017A novel BCR-ABL1 fusion gene with genetic heterogeneity indicates a good prognosis in a chronic myeloid leukemia case.33
    360869542023Targeting the PTP1B-Bcr-Abl1 interaction for the degradation of T315I mutant Bcr-Abl1 in chronic myeloid leukemia.32
    347716342021Droplet Digital PCR for BCR-ABL1 Monitoring in Diagnostic Routine: Ready to Start?31
    299767452018BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia.28
    381539132024Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL.23
    388219402024Imatinib with intensive chemotherapy in AML with t(9;22)(q34.1;q11.2)/BCR::ABL1. A DATAML registry study.22
    361955702023Hypoxia-inducible factor 1α inhibitor induces cell death via suppression of BCR-ABL1 and Met expression in BCR-ABL1 tyrosine kinase inhibitor sensitive and resistant chronic myeloid leukemia cells.22
    341104622021Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-ABL1(T315I) and BCR-ABL1(T315I-E255K).22
    374960242023FISH-negative BCR::ABL1-positive e19a2 chronic myeloid leukaemia: the most cryptic of insertions.21
    321279502020BCR-ABL1 transcript decline ratio combined BCR-ABL1(IS) as a precise predictor for imatinib response and outcome in the patients with chronic myeloid leukemia.21
    338145002021BCR/ABL1-positive B-lymphoblastic Lymphoma Successfully Treated with Dasatinib-combined Chemotherapy.20
    389069622024Asciminib antagonizes transplantable BCR::ABL1-positive lymphoid blast crisis in vivo by targeting malignant stem cells.20
    301259552018Consensus on BCR-ABL1 reporting in chronic myeloid leukaemia in the UK.19
    357566862022Successful Preservation of Native BCR::ABL1 in Chronic Myeloid Leukemia Primary Leukocytes Reveals a Reduced Kinase Activity.18
    258803912015Clonal distribution of BCR-ABL1 mutations and splice isoforms by single-molecule long-read RNA sequencing.17
    316443232020BCR-ABL1-like B-Acute Lymphoblastic Leukemia/Lymphoma: A Comprehensive Review.0
    350210692022Development of asciminib, a novel allosteric inhibitor of BCR-ABL1.0
    330963222020The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase.0
    386434922024BCR::ABL1 kinase N-lobe mutants confer moderate to high degrees of resistance to asciminib.0
    371839662023Ultrasensitive NGS MRD assessment in Ph+ ALL: Prognostic impact and correlation with RT-PCR for BCR::ABL1.0
    383947742024Beyond BCR::ABL1-The Role of Genomic Analyses in the Management of CML.0
    390289282024Significance of Measurable Residual Disease in Adult Philadelphia Chromosome-Positive ALL: A GRAAPH-2014 Study.0
    330389882020CML - Not only BCR-ABL1 matters.0
    348186442022BCR/ABL1-Like Acute Lymphoblastic Leukemia: From Diagnostic Approaches to Molecularly Targeted Therapy.0
    296966942018Laboratory testing in BCR-ABL1-like (Philadelphia-like) B-lymphoblastic leukemia/lymphoma.0
    282220162017A review of the challenge in measuring and standardizing BCR-ABL1.0
    310699762019BCR-ABL1-like B-lymphoblastic leukemia/lymphoma: Review of the entity and detection methodologies.0
    305617552019BCR/ABL1-like acute lymphoblastic leukemia: How to diagnose and treat?0
    279048892017Reactive oxygen species in BCR-ABL1-expressing cells - relevance to chronic myeloid leukemia.0
    356093362022The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved Drug.0
    316963822019The Hidden Pathogenesis of CML: Is BCR-ABL1 the First Event?0
    262972642015Mutations in the BCR-ABL1 Kinase Domain and Elsewhere in Chronic Myeloid Leukemia.0
    244073762014Genetic events other than BCR-ABL1.0
    241318882014Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia.0
    351717272022MUC4 expression by immunohistochemistry is a specific marker for BCR-ABL1+ and BCR-ABL1-like B-lymphoblastic leukemia.0
    190021922008BCR-ABL1-positive CML and BCR-ABL1-negative chronic myeloproliferative disorders: some common and contrasting features.0
    274120402017Measurement of BCR-ABL1 transcripts on the International Scale in the United States: current status and best practices.0
    387347862024TIF1β activates leukemic transcriptional program in HSCs and promotes BCR::ABL1-induced myeloid leukemia.0
    271316222016Early BCR-ABL1 Reduction Is Predictive of Better Event-free Survival in Patients With Newly Diagnosed Chronic Myeloid Leukemia Treated With Any Tyrosine Kinase Inhibitor.0
    374799512023Mitochondrial Dysfunction in Cardiotoxicity Induced by BCR-ABL1 Tyrosine Kinase Inhibitors -Underlying Mechanisms, Detection, Potential Therapies.0
    280357332017Frequency of rare BCR-ABL1 fusion transcripts in chronic myeloid leukemia patients.0
    341853932021BCR-ABL1 p210 screening for chronic myeloid leukemia in patients with peripheral blood cytoses.0
    373023522023Genetic alterations in the BCR-ABL1 fusion gene related to imatinib resistance in chronic myeloid leukemia.0
    370788962023Management of chronic myeloid leukaemia: current treatment options, challenges, and future strategies.0
    392170002025SOHO State of the Art Updates and Next Questions | Approach to BCR::ABL1-Like Acute Lymphoblastic Leukemia.0
    283310562017Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology.0
    243678932014Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1.0
    345066222022Sequential Development of JAK2V617F Mutation and BCR-ABL1 Fusion in Individual Patients With Myeloproliferative Neoplasms.0
    392919322024Low-Level BCR::ABL1 Transcript at Diagnosis in Childhood Leukemia: A 10-Year Single Institution Study.0
    393746392025New practice of BCR::ABL1 standardization system based on p210 and p190 BCR::ABL1 reference materials.0
    258140772015Natural course and biology of CML.0
    391678242024Comparative analysis of BCR::ABL1 p210 mRNA transcript quantification and ratio to ABL1 control gene converted to the International Scale by chip digital PCR and droplet digital PCR for monitoring patients with chronic myeloid leukemia.0
    317075402020Low prevalence of the BCR-ABL1 fusion gene in a normal population in southern Sarawak.0
    397434102024A Review of Clonal Relationships in Myeloproliferative Neoplasms With Co-Mutations of JAK2, CALR or MPL and BCR::ABL1.0
    378719002024IGJ and SPATS2L immunohistochemistry sensitively and specifically identify BCR::ABL1+ and BCR::ABL1-like B-acute lymphoblastic leukaemia.0
    328715882021Early BCR-ABL1 kinetics are predictive of subsequent achievement of treatment-free remission in chronic myeloid leukemia.0
    352964472022The Clinical Significance of BCR-ABL1 Mutations in Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation.0
    284375522017BCR-ABL1 transcript types showed distinct laboratory characteristics in patients with chronic myeloid leukemia.0
    221187442011Chronic myeloid leukemia: current perspectives.0

    Bibliography

    No bibliography items were found for this article.

    Summary

    Note

    Although the same hybrid genes issued from ABL and BCR are the hallmark of the t(9;22) translocation, this translocation may be seen in the following diseases: CML, AML, and ALL, and will therefore be described in the 3 different situations: t(9;22)(q34;q11) in CML, t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in AML t(9;22)(q34;q11) in ALL 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 ; Jean-Loup Huret

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

    Atlas Genet Cytogenet Oncol Haematol. 1997-09-01

    Online version: http://atlasgeneticsoncology.org/haematological/1024/t(9