Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   
X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

t(9;22)(q34;q11) in ALL

Identity

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, ANLL, 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 ANLL 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 ANLL 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 Name ABL
Location 9q34
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 Name BCR
Location 22q11
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
      

    External links

    Other databaset(9;22)(q34;q11) in ALL Mitelman database (CGAP - NCBI)
    Other databaseABL/BCR translocation (9/22) (Bari)

    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

    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
     
    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
     

    Contributor(s)

    Written09-1997Jean-Loup Huret

    Citation

    This paper should be referenced as such :
    Huret JL . t(9;22)(q34;q11) in ALL. Atlas Genet Cytogenet Oncol Haematol. Septem ber 1997 .
    URL : http://AtlasGeneticsOncology.org/Anomalies/t0922ALL.html

    This paper is referenced by INIST as such :
    http://documents.irevues.inist.fr/bitstream/handle/2042/32035/09-1997-t0922ALL.pdf   [ Bibliographic record ]

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Sat Mar 9 12:37:38 CET 2013
    Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us

    jlhuret@AtlasGeneticsOncology.org.