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

Identity

ICD-Topo	C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho	9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Atlas_Id	1022
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: chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), and acute lymphocytic leukemia (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 CML 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	CML: all CML have a t(9;22), at least at the molecular level (see below); but not all t(9;22) are found in CML, as already noted
Phenotype / cell stem origin	Evidence exists for the involvement of the most primitive and quiescent hematopoietic stem cell compartiment (CD34+/CD38-, Thy1+): t(9;22) is found in myeloid progenitor and in B-lymphocytes progenitors, but, involvement of the T-cell lineage is extremely rare
Epidemiology	annual incidence: 10/106 (from 1/106 in childhood to 30/106 after 60 yrs); median age: 30-60 yrs; sex ratio: 1.2M/1F
Clinics	splenomegaly; chronic phase (lasts about 3 yrs) with maintained cell's normal activities, followed by accelerated phase(s) (blasts still < 15%), and blast crisis (BC-CML) with blast cells > 30%; blood data: WBC: 100 X 109/l and more during chronic phase, with basophilia; a few blasts; thrombocytosis may be present; low leucocyte alkaline phosphatases; typical acute leukaemia (AL) blood data at the time of myeloid or lymphoid -type blast crisis
Cytology	hyperplastic bone marrow; granulocytes proliferation, with maturation; followed by typical AL cytology (see t(9;22)(q34;q11)/AML, and t(9;22)(q34;q11)/ALL)
Treatment	aIFN therapy or allogeneic bone marrow transplantation (BMT), donor leukocytes infusions
Prognosis	median survival: 4 yrs with conventional therapy (hydroxyurea, busulfan), 6 yrs with aIFN therapy; allogeneic bone marrow transplantation may cure the patient; otherwise, the best treatment to date associates interferon a, hydroxyurea and cytarabine

Cytogenetics

	835J22 + 1132H12 and 72M14 Cohybridization of (835J22 + 1132H12; ABL) and 72M14 (BCR) on a CML patient carrying the t(9;22) translocation. Note the splitting of (835J22 + 1132H12) (red signal) and the colocalization on Ph chromosome (Ph) -Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
Cytogenetics Morphological	the chromosomal anomaly persists during remission, in contrast with acute leukemia (AL) cases
Cytogenetics Molecular	is a useful tool for diagnostic ascertainment in the case of 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
	Cryptic insertion of BCR within chromosome 9. FISH using the Vysis LSI BCR/ABL Dual Color, Dual Fusion Translocation Probe - Courtesy Karolien Beel, Geneviève Ameye and Lucienne Michaux, CME, UZ Leuven
Additional anomalies	1. may be present at diagnosis (in 10%, possibly with unfavourable significance), or may appear during course of the disease, they do not indicate the imminence of a blast crisis, although these additional anomalies also emerge frequently at the time of acute transformation; 2. these are: +der(22), +8, i(17q), +19, most often, but also: +21, -Y, -7, -17, +17; acute transformation can also be accompanied with t(3;21) (q26;q22) (1% of cases); near haploidy can occur; of note, although rare, is the occurrence of chromosome anomalies which are typical of a given BC phenotype (e.g. t(15;17) in a promyelocytic transformation, dic(9;12) in a CD10+ lymphoblastic BC ...); +8, +19, +21, and i(17q) occur more often in myeloid -rather than lymphoid- blast crises
Variants	t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variable chromosome, are found in 5-10% of cases; however, 9q34-3'ABL always joins 22q11-5'BCR in true CML; the third chromosome and breakpoint is, at times, not random. In a way, masked Philadelphia chromosomes (see above) are also variants.

Genes involved and Proteins

Gene Name	ABL1 (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 Name	BCR (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	1. 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; 2. 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; 3. breakpoint in BCR is in a narrow region, therefore 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	8.5 kb mRNA, resulting in a 210 KDa chimeric protein
Detection	RT-PCR for minimal residual disease detection

Fusion Protein

Description	P210 with the first 902 or 927 amino acids from BCR; BCR/ABL has a cytoplasmic localization, in contrast with ABL, mostly nuclear. It is now clearly established that BCR-ABL is the oncogene responsible for the occurrence of CML . 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	A- Major molecular pathways activated by BCR-ABL. BCR/ABL activates RAS signaling through the GRB2 adaptor molecule which interacts specifically with the Y177 of BCR.. PI3-K (phosphatidyl inositol 3' kinase) pathway is also activated with secondary activation of the AKT/PKB pathway. Integrity of transcription machinery induced by MYC is necessary for the transforming action of BCR-ABL. More recently, activation of STAT (Signal transducers and activators of transcription) molecules has been described as a major molecular signaling event induced by BCR-ABL, with activation of essentially STAT5, 1, and 6. Activation of the molecules of the focal adhesion complex (PAXILLIN, FAK) by BCR-ABL requires the role of the adaptor molecule CRK-L. BCR-ABL activates negative regulatory molecules such as PTP1B and Abi-1 and their inactivation could be associated with progression into blast crisis. B- Correlations between molecular pathways and leukemic phenotype observed in primary CML cells or in BCR-ABL-transduced cells are currently limited. BCR-ABL has anti-apoptotic activity (PI63K/Akt/STAT5) . BCR/ABL induces cell adhesive and migratory abnormalities in vitro in the presence of fibronection or in transwell assays (Abnormal integrin signaling/FAK/CRK-L/Abnormal response to chemokine SDF-1). BCR-ABL induces a dose-effect relationship in CML cells with increased BCR-ABL mRNA during progression into blast crisis, with induction of genetic instability. Molecular events associated with blast crisis: P53 mutation, methylation of ABL promoter, telomere shortening, Abi-1 inactivation.

To be noted

1. blast crisis is sometimes at the first onset of CML, and those cases may be undistinguishable from true ALL or AML with t(9;22) and P210 BCR/ABL hybrid; 2. JCML (juvenile chronic myelogenous leukaemia) is not the juvenile form of chronic myelogenous leukaemia: there is no t(9;22) nor BCR/ABL hybrid in JCML, and clinical features (including a worse prognosis) are not similar to those found in CML; 3. so called BCR/ABL negative CML should not be called so! 4. P53 is altered in 1/3 of BC-CML cases 5. Most recent developments: Evidence of telomere shortening in CML cells during progression into blast crisis.

Bibliography

BCR-ABL and constitutively active erythropoietin receptor (cEpoR) activate distinct mechanisms for growth factor-independence and inhibition of apoptosis in Ba/F3 cell line.

Ahmed M, Dusanter-Fourt I, Bernard M, Mayeux P, Hawley RG, Bennardo T, Novault S, Bonnet ML, Gisselbrecht S, Varet B, Turhan AG

Oncogene. 1998 ; 16 (4) : 489-496.

PMID 9484838

Bcr/Abl expression stimulates integrin function in hematopoietic cell lines.

Bazzoni G, Carlesso N, Griffin JD, Hemler ME

The Journal of clinical investigation. 1996 ; 98 (2) : 521-528.

PMID 8755665

Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry.

Brümmendorf TH, Holyoake TL, Rufer N, Barnett MJ, Schulzer M, Eaves CJ, Eaves AC, Lansdorp PM

Blood. 2000 ; 95 (6) : 1883-1890.

PMID 10706851

Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway.

Dai Z, Quackenbush RC, Courtney KD, Grove M, Cortez D, Reuther GW, Pendergast AM

Genes & development. 1998 ; 12 (10) : 1415-1424.

PMID 9585502

Chronic myelogenous leukemia.

Enright H, McGlave PB

Current opinion in hematology. 1995 ; 2 (4) : 293-299.

PMID 9372010

Chronic myelogenous leukemia: biology and therapy.

Gale RP, Grosveld G, Canaani E, Goldman JM

Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1993 ; 7 (4) : 653-658.

PMID 8464245

The function of BCR/ABL and related proto-oncogenes.

Gotoh A, Broxmeyer HE

Current opinion in hematology. 1997 ; 4 (1) : 3-11.

PMID 9050373

Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group.

Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J

The New England journal of medicine. 1997 ; 337 (4) : 223-229.

PMID 9227927

Molecular insights into the Philadelphia translocation.

Heisterkamp N, Groffen J

Hematologic pathology. 1991 ; 5 (1) : 1-10.

PMID 2050600

Complex translocations, simple variant translocations and Ph-negative cases in chronic myelogenous leukaemia.

Huret JL

Human genetics. 1990 ; 85 (6) : 565-568.

PMID 2227945

P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members.

Ilaria RL Jr, Van Etten RA

The Journal of biological chemistry. 1996 ; 271 (49) : 31704-31710.

PMID 8940193

The molecular pathology of chronic myelogenous leukaemia.

Kurzrock R, Talpaz M

British journal of haematology. 1991 ; 79 Suppl 1 : 34-37.

PMID 1931706

Protein tyrosine phosphatase 1B antagonizes signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo.

LaMontagne KR Jr, Flint AJ, Franza BR Jr, Pandergast AM, Tonks NK

Molecular and cellular biology. 1998 ; 18 (5) : 2965-2975.

PMID 9566916

Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Français de Cytogénétique Hématologique (GFCH).

Martiat P, Michaux JL, Rodhain J

Blood. 1991 ; 78 (1) : 205-211.

PMID 2070054

Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia.

Oda T, Heaney C, Hagopian JR, Okuda K, Griffin JD, Druker BJ

The Journal of biological chemistry. 1994 ; 269 (37) : 22925-22928.

PMID 8083188

Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway.

Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, Wasik MA, Tsichlis PN, Calabretta B

The EMBO journal. 1997 ; 16 (20) : 6151-6161.

PMID 9321394

Prognostic significance of additional cytogenetic abnormalities at diagnosis of Philadelphia chromosome-positive chronic granulocytic leukemia.

Sokal JE, Gomez GA, Baccarani M, Tura S, Clarkson BD, Cervantes F, Rozman C, Carbonell F, Anger B, Heimpel H

Blood. 1988 ; 72 (1) : 294-298.

PMID 3164637

Citation

This paper should be referenced as such :

Turhan, AG

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

Atlas Genet Cytogenet Oncol Haematol. 2000;4(4):205-208.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Anomalies/t0922CMLID1022.html

History of this paper:

Huret, JL. t(10;11)(p12;q23). Atlas Genet Cytogenet Oncol Haematol. 1997;1(2):101-101.

http://documents.irevues.inist.fr/bitstream/handle/2042/32071/12-1997-t0922CML.pdf

Other genes implicated (Data extracted from papers in the Atlas) [ 12 ]

Genes	ABL1	AKT1	BACH2	BCL6	BCR	BTK	FIP1L1	GFI1B	PRKCI	SIRT1
	SRC	TGFBR2

Translocations implicated (Data extracted from papers in the Atlas)

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

External links

Mitelman database	t(9;22)(q34;q11)
arrayMap (UZH-SIB Zurich)	Topo ( C42) Morph ( 9975/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
Other database	ABL/BCR translocation (9/22) (Bari)

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed
All articles	automatic search in PubMed

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