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

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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 database t(9;22)(q34;q11) in ALL Mitelman database (CGAP - NCBI)

Other database t(9;22)(q34;q11) in ALL CancerChromosomes (NCBI)

Other database ABL/BCR translocation (9/22) (Bari)

Probe ABL (9q34) in normal cells (Bari)

Probe BCR (22q11.2) in normal cells (Bari)

Other database	t(9;22)(q34;q11) in ALL	Mitelman database (CGAP - NCBI)
Other database	t(9;22)(q34;q11) in ALL	CancerChromosomes (NCBI)
Other database	ABL/BCR translocation (9/22) (Bari)
Probe	ABL (9q34) in normal cells (Bari)
Probe	BCR (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 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)

Written 09-1997 Jean-Loup Huret

Citation

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

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

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For comments and suggestions or contributions, please contact us

j.l.huret@chu-poitiers.fr.

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).

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 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

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

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

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