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

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: chronic myelogenous leukemia (CML), acute non lymphocytic leukemia (ANLL), 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 ANLL 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)/ANLL, 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
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	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	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.

External links

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

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

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Contributor(s)

Written	12-1997	Jean-Loup Huret
		Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated	10-2000	Ali G Turhan
		Translational Research - Cell Therapy, Laboratory, INSTITUT GUSTAVE ROUSSY, INSERM U. 362, 1 - 39, rue Camille Desmoulins, 94805 VILLEJUIF CEDEX - FRANCE

Citation

This paper should be referenced as such :

Huret JL . t(9;22)(q34;q11) in CML. Atlas Genet Cytogenet Oncol Haematol. December 1997 . URL : http://AtlasGeneticsOncology.org/Genes/t0922CML.html

Turhan AG . t(9;22)(q34;q11) in CML. Atlas Genet Cytogenet Oncol Haematol. October 2000 . URL : http://AtlasGeneticsOncology.org/Genes/t0922CML.html

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