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

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 ANLL 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 ANLL
Phenotype / cell stem origin mostly M1 or M2 ANLL
Epidemiology 3% of ANLL; 1% in childhood ANLL
Prognosis is very poor

Cytogenetics

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

Genes involved and Proteins

Gene Name ABL BCR
Location 9q34 22q11
Dna / Rna alternate splicing (1a and 1b) in 5' various splicings
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 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 ANLL Mitelman database (CGAP - NCBI)
    Other databaset(9;22)(q34;q11) in ANLL CancerChromosomes (NCBI)
    Other databaseABL/BCR translocation (9/22) (Bari)
    ProbeABL (9q34)  in normal cells (Bari)
    ProbeBCR (22q11.2) in normal cells (Bari)

    To be noted

    blast crisis is sometimes at the first onset of CML, and those cases may be undistinguishable from true ANLL 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
     

    Contributor(s)

    Written09-1997Jean-Loup Huret

    Citation

    This paper should be referenced as such :
    Huret JL . t(9;22)(q34;q11) in ANLL. Atlas Genet Cytogenet Oncol Haematol. September 1997 .
    URL : http://AtlasGeneticsOncology.org/Anomalies/t0922ANL.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Mon May 12 18:12:48 2008

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