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

2000-10-01   Ali G Turhan  

1.Translational Research - Cell Therapy, Laboratory, INSTITUT GUSTAVE ROUSSY, INSERM U. 362, 1 - 39, rue Camille Desmoulins, 94805 VILLEJUIF CEDEX - FRANCE
2.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Clinics and Pathology

Disease

CML: all CML have a t(9;22), at least at the molecular level (seebelow); but not all t(9;22) are found in CML, as already noted

Phenotype stem cell origin

Evidence exists for the involvement of the most primitive and quiescent hematopoietic stem cell compartiment (CD34+/CD38-, Thy1+): t(9;22) is found in myeloid progenitor and in B-lymphocytes progenitors, but, involvement of the T-cell lineage is extremely rare

Epidemiology

annual incidence: 10/106 (from 1/106 in childhood to 30/106after 60 yrs); median age: 30-60 yrs; sex ratio: 1.2M/1F

Clinics

splenomegaly; chronic phase (lasts about 3 yrs) with maintained cells normal activities, followed by accelerated phase(s) (blasts still < 15%), and blast crisis (BC-CML) with blast cells > 30%; blood data: WBC: 100 X 109/l and more during chronic phase, with basophilia; a few blasts; thrombocytosis may be present; low leucocyte alkaline phosphatases; typical acute leukaemia (AL) blood data at the time of myeloid or lymphoid -type blast crisis

Cytology

hyperplastic bone marrow; granulocytes proliferation, with maturation; followed by typical AL cytology (see t(9;22)(q34;q11)/AML, and t(9;22)(q34;q11)/ALL)

Treatment

aIFN therapy or allogeneic bone marrow transplantation (BMT), donor leukocytes infusions

Prognosis

median survival: 4 yrs with conventional therapy (hydroxyurea, busulfan), 6 yrs with aIFN therapy; allogeneic bone marrow transplantation may cure the patient; otherwise, the best treatment to date associates interferon a, hydroxyurea and cytarabine

Cytogenetics

Cytogenetics morphological

the chromosomal anomaly persists during remission, in contrast with acute leukemia (AL) cases

Cytogenetics molecular

is a useful tool for diagnostic ascertainment in the case of a masked Philadelphia chromosome, where chromosomes 9 and 22 all appear to be normal, but where cryptic insertion of 3 ABL within a chromosome 22 can be demonstrated

Additional anomalies

1. may be present at diagnosis (in 10%, possibly with unfavourable significance), or may appear during course of the disease, they do not indicate the imminence of a blast crisis, although these additional anomalies also emerge frequently at the time of acute transformation;
2. these are: +der(22), +8, i(17q), +19, most often, but also: +21, -Y, -7, -17, +17; acute transformation can also be accompanied with t(3;21) (q26;q22) (1% of cases); near haploidy can occur; of note, although rare, is the occurrence of chromosome anomalies which are typical of a given BC phenotype (e.g. t(15;17) in a promyelocytic transformation, dic(9;12) in a CD10+ lymphoblastic BC ...); +8, +19, +21, and i(17q) occur more often in myeloid -rather than lymphoid- blast crises

Variants

t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variable chromosome, are found in 5-10% of cases; however, 9q34-3ABL always joins 22q11-5BCR in true CML; the third chromosome and breakpoint is, at times, not random. In a way, masked Philadelphia chromosomes (see above) are also variants.
Atlas Image
835J22 + 1132H12 and 72M14 Cohybridization of (835J22 + 1132H12; ABL) and 72M14 (BCR) on a CML patient carrying the t(9;22) translocation. Note the splitting of (835J22 + 1132H12) (red signal) and the colocalization on Ph chromosome (Ph) -Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
Atlas Image
Cryptic insertion of BCR within chromosome 9. FISH using the Vysis LSI BCR/ABL Dual Color, Dual Fusion Translocation Probe - Courtesy Karolien Beel, Geneviu00e8ve Ameye and Lucienne Michaux, CME, UZ Leuven

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 (SRC homology) domains; N-term SH3 and SH2 - SH1 (tyrosine kinase) - DNA binding motif - actin binding domain C-term; widely expressed; localisation is mainly 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 domain, SH2 binding, and C-term domain which functions as a GTPase activating protein for p21rac; widely expressed; cytoplasmic localisation; protein kinase; probable role in signal transduction

Result of the Chromosomal Anomaly

Description

1. the crucial event lies on der(22), id est 5 BCR/3 ABL hybrid gene is pathogenic, while ABL/BCR may or may not be expressed;
2. breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5 of 1b, or 3 of 1a, but always 5 of exon 2;
3. breakpoint in BCR is in a narrow region, therefore called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5 of M-bcr; most breakpoints being either between b2 and b3, or between b3 and b4

Transcript

8.5 kb mRNA, resulting in a 210 KDa chimeric protein

Detection protocole

RT-PCR for minimal residual disease detection

Description

P210 with the first 902 or 927 amino acids from BCR; BCR/ABL has a cytoplasmic localization, in contrast with ABL, mostly nuclear. It is now clearly established that BCR-ABL is the oncogene responsible for the occurrence of CML . The hybrid protein has an increased protein kinase activity compared to ABL: 3BP1 (binding protein) binds normal ABL on SH3 domain, which prevents SH1 activation; with BCR/ABL, the first (N-terminal) exon of BCR binds to SH2, hidding SH3 which, as a consequence, cannot be bound to 3BP1; thereof, SH1 is activated

Oncogenesis

  • A- Major molecular pathways activated by BCR-ABL.
  • BCR/ABL activates RAS signaling through the GRB2 adaptor molecule which interacts specifically with the Y177 of BCR..
  • PI3-K (phosphatidyl inositol 3 kinase) pathway is also activated with secondary activation of the AKT/PKB pathway.
  • Integrity of transcription machinery induced by MYC is necessary for the transforming action of BCR-ABL.
  • More recently, activation of STAT (Signal transducers and activators of transcription) molecules has been described as a major molecular signaling event induced by BCR-ABL, with activation of essentially STAT5, 1, and 6.
  • Activation of the molecules of the focal adhesion complex (PAXILLIN, FAK) by BCR-ABL requires the role of the adaptor molecule CRK-L.
  • BCR-ABL activates negative regulatory molecules such as PTP1B and Abi-1 and their inactivation could be associated with progression into blast crisis.
  • B- Correlations between molecular pathways and leukemic phenotype observed in primary CML cells or in BCR-ABL-transduced cells are currently limited.
  • BCR-ABL has anti-apoptotic activity (PI63K/Akt/STAT5) .
  • BCR/ABL induces cell adhesive and migratory abnormalities in vitro in the presence of fibronection or in transwell assays (Abnormal integrin signaling/FAK/CRK-L/Abnormal response to chemokine SDF-1).
  • BCR-ABL induces a dose-effect relationship in CML cells with increased BCR-ABL mRNA during progression into blast crisis, with induction of genetic instability.
  • Molecular events associated with blast crisis: P53 mutation, methylation of ABL promoter, telomere shortening, Abi-1 inactivation.

    • 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
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    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
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    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
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    262911292015MAPK15 mediates BCR-ABL1-induced autophagy and regulates oncogene-dependent cell proliferation and tumor formation.47
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    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
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    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
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    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
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    Bibliography

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    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: chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), and acute lymphocytic leukemia (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 AMLt(9;22)(q34;q11) in CML 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

    Ali G Turhan

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

    Atlas Genet Cytogenet Oncol Haematol. 2000-10-01

    Online version: http://atlasgeneticsoncology.org/haematological/1022/t(9;22)(q34;q11)-bcr-abl1-in-cml

    Historical Card

    1997-12-01 t(9;22)(q34;q11) BCR/ABL1 in CML by  Jean-Loup Huret,Jean-Loup Huret 

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