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 , 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
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

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 , 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)
  • Transcript

    7 or 8.5 kb

    Description

    190 or 210 kDa (see above); BCR/ABL has a cytoplasmic

    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

    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;22)(q34;q11)-bcr-abl1-in-all