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

Written1997-09Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9806/3 Mixed phenotype acute leukaemia with t(9;22)(q34;q11.2); BCR-ABL1
ICD-Morpho 9812/3 B lymphoblastic leukaemia/lymphoma with t(9:22)(q34;q11.2); BCR-ABL1
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
Atlas_Id 1024
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.
 
  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).

Clinics and Pathology

Disease ALL
Phenotype / cell stem 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 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 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 variable chromosome, may be found, as in CML

Genes involved and Proteins

Gene NameABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)
Location 9q34.12
Dna / Rna alternate splicing (1a and 1b) in 5'
Protein 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 NameBCR (Breakpoint cluster region)
Location 22q11.23
Dna / Rna various splicings
Protein 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

Hybrid gene
Description
  • 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;
  • 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; - breakpoint in BCR is either (as in ALL cases): 1- in the same region as in CML, 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 is 8.5 kb long; this results in a 210 KDa chimeric protein (P210), with the first 902 or 927 amino acids from BCR; 2- in a 35 kb region between exons 1 and 2, called m-bcr (minor breakpoint cluster region), -> 7 kb mRNA, resulting in a 190 KDa protein (P190), with the 427 N-terminal amino acids from BCR
  • Transcript 7 or 8.5 kb
      
    Fusion Protein
    Description 190 or 210 kDa (see above); BCR/ABL has a cytoplasmic localization, in contrast with ABL, mostly nuclear; this may have a carcinogenetic role. 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 1- proliferation is induced: there is activation by BCR/ABL of Ras signal transduction pathway via it's linkage to son-of-sevenless (SOS), a Ras activator; PI3-K (phosphatidyl inositol 3' kinase) pathway is also activated; MYC as well; 2- BCR/ABL inhibits apoptosis; 3- BCR/ABL provokes cell adhesive abnormalities: impaired adherence to bone marrow stroma cells, which allows unregulated proliferation of leukaemic progenitors
      

    To be noted

    blast crisis is sometimes at the first onset of CML, and those cases may be undistinguishable from true ALL with t(9;22) and P210 BCR/ABL hybrid.

    Bibliography

    The function of BCR/ABL and related proto-oncogenes.
    Gotoh A, Broxmeyer HE
    Current opinion in hematology. 1997 ; 4 (1) : 3-11.
    PMID 9050373
     
    Molecular insights into the Philadelphia translocation.
    Heisterkamp N, Groffen J
    Hematologic pathology. 1991 ; 5 (1) : 1-10.
    PMID 2050600
     
    The molecular pathology of chronic myelogenous leukaemia.
    Kurzrock R, Talpaz M
    British journal of haematology. 1991 ; 79 Suppl 1 : 34-37.
    PMID 1931706
     
    Prognostic implications of breakpoint and lineage heterogeneity in Philadelphia-positive acute lymphoblastic leukemia: a review.
    Secker-Walker LM, Craig JM
    Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1993 ; 7 (2) : 147-151.
    PMID 8426467
     

    Citation

    This paper should be referenced as such :
    Huret, JL
    t(9;22)(q34;q11) in ALL
    Atlas Genet Cytogenet Oncol Haematol. 1997;1(1):26-28.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Anomalies/t0922ALLID1024.html


    Other genes implicated (Data extracted from papers in the Atlas) [ 7 ]

    Genes ABL1 BCL6 BCR BLNK GRB2 IRS1

    Translocations implicated (Data extracted from papers in the Atlas)

     t(9;22)(q34;q11) BCR/ABL1 in ALL

    External links

    Mitelman databaset(9;22)(q34;q11) [Case List]    t(9;22)(q34;q11) [Association List] Mitelman database (CGAP - NCBI)
    arrayMapTopo ( C42) Morph ( 9806/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
    arrayMapTopo ( C42) Morph ( 9812/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
    arrayMapTopo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
    arrayMapTopo ( C42) Morph ( 9837/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
     
     
    Other databaseABL/BCR translocation (9/22) (Bari)
    Disease databaset(9;22)(q34;q11) BCR/ABL1 in ALL
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed
    All articlesautomatic search in PubMed


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