Molecular cytogenetics of chronic myeloid leukemia with atypical t(6:9)(p23:q34) translocation
Academic Department of Haematology and Cytogenetics, Institute of Cancer Research/Royal Marsden Hospital, Surrey, UK. Leukemia
(Impact Factor: 10.43).
We report the molecular cytogenetic analysis of a case of Philadelphia (Ph)-negative, BCR-positive chronic myeloid leukemia (CML) which appeared by conventional cytogenetics to have a t(6;9)(p23;q34) as the sole cytogenetic abnormality. Neither conventional nor pulse-field Southern blots detected any rearrangement of the DEK or CAN genes which are often fused in acute myeloid leukemia (AML) with t(6;9)(p23;q34). However, rearrangements of both BCR and ABL genes were detected. The breakpoint in BCR was located in the major translocation cluster region between exons b1 and b3. ABL rearrangements were detected with an ABL exon 1B probe and with a probe located 5' of the entire ABL gene. Comigration between the rearranged fragments obtained with M-bcr-5' and ABL exon 1B probes was observed, implying that the entire ABL gene was fused to the 5' part of the BCR gene. Fluorescence in situ hybridization (FISH) analyses using BCR and ABL probes showed that in 20% of metaphases BCR and ABL signals were present on one chromosome 6 at 6p23, whilst in 80% of metaphases BCR and ABL signals were identified on both copies of chromosome 6. Furthermore, FISH analysis with a whole-chromosome 22 paint demonstrated that chromosome 22 material was present on both copies of chromosome 6. These data indicate a complex Philadelphia translocation involving chromosome band 6p23 and duplication of the whole aberrant chromosome. The nature of the gene locus on 6p23, involved in this rearrangement, remains unknown. A similar translocation has been previously reported in a case of CML, which also lacked DEK and CAN gene rearrangements implying that abnormalities of 6p23 involving genes other than DEK may be a recurrent abnormality in CML.
Available from: ncbi.nlm.nih.gov
- "Translocations with chromosome 6 often occur as primary aberration in AML. Nevertheless, it has been shown that a translocation t(6;9)(p23;q34) in CML is not the same as in AML and it was suggested that additional genes on 6p23 may be important for the pathogenesis of CML . "
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ABSTRACT: Unregulated proliferation of mainly myeloid bone marrow cells and genetic changes in the hematopoietic stem cell system are important features in Chronic Myeloid Leukemia (CML). In clinical diagnosis of CML, classical banding techniques, fluorescence in situ hybridization (FISH) probing for the Philadelphia chromosome (Ph) or polymerase chain reaction amplifying the fusion products of the BCR-ABL fusion are state of the art techniques. Nevertheless, the genome of CML patients harbors many more cytogenetic changes. These might be hidden in subpopulations due to clonal events or involved in extremely complex aberrations. To identify these additional changes, several cytogenetic and molecular genetic techniques could be applied. Nevertheless, it has been proposed that identifying these aberrations is time consuming and costly and since they cannot be converted into a benefit for the patients, the necessity to perform these investigations has been questioned. In the times where highly specialized medicine is advancing into several areas of cancer, this attitude needs to be reassessed. Therefore, we looked at the usefulness of a combination of different techniques to unravel the genetic changes in CML patients and to identify new chromosomal aberrations, which potentially can be correlated to different stages of the disease and the strength of therapy resistance. We are convinced that the combination of these techniques could be extremely useful in unraveling even the most complex karyotypes and in dissecting different clones contributing to the disease. We propose that by doing so, this would improve CML diagnostic and prognostic findings, especially with regard to CML resistance mechanisms and new therapeutic strategies.
Current Genomics 09/2012; 13(6):471-6. DOI:10.2174/138920212802510466 · 2.34 Impact Factor
Available from: Takayuki Saitoh
- "Pearson et al (1985) first reported an association between the t(6;9)-AML and bone marrow basophilia, which is now viewed as a common feature in haematological malignancies with t(6;9). The mechanism by which basophilia develops, and whether or not this finding is really specific for the t(6;9) leukaemia, is still unclear (Lillington et al, 1993; Jadayel et al, 1995). The translocation t(6;9) results in a dek±can gene fusion (von Lindern et al, 1992). "
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ABSTRACT: The translocation t(6;9)(p23;q34) is detected infrequently in subtypes of haematological malignancies including acute myelogenous leukaemia (AML) and myelodysplastic syndrome (MDS). Although the t(6;9) leukaemia is commonly associated with bone marrow basophilia, the cytological characteristics of leukaemic cells are unclear. In the current study, we examined the in vitro effects of several cytokines on growth and differentiation of t(6;9) leukaemic cells. Isolated bone marrow mononuclear cells from four patients with t(6;9) (two MDS and two AML) were cultured for 14 d in the presence or absence of each cytokine. At the end of culture, viable cells were counted, and their histology was examined. Bone marrow cells obtained from 22 patients (10 AML, six AML from MDS, six MDS) lacking t(6;9) were used as controls. Compared with control cultures, significantly higher numbers of blasts appeared in the culture of bone marrow cells from t(6;9)-positive patients in response to stimulation with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF) or interleukin 3 (IL-3). Stem cell factor (SCF) had little effect. Neutrophil counts were also significantly increased in the presence of G-CSF or IL-3. SCF and IL-3 were potent in increasing basophil counts from t(6;9)-positive cultures. These findings suggest that bone marrow cells obtained from t(6;9) patients are highly sensitive to growth- and/or differentiation-promoting cytokines. Special attention should be paid to the use of "therapeutic" cytokines in these patients.
British Journal of Haematology 01/2002; 115(4):812-6. DOI:10.1046/j.1365-2141.2001.03224.x · 4.71 Impact Factor
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ABSTRACT: Ahmed IH. Analysis of variant translocation t(4;9;22) by a fluorescence in situ hybridization(FISH) in a case of Chronic myelocytocytic leukemia. Case Study and Case Report 2012; 2(2): 46 -52. ABSTRACT Chronic myelocyctic leukemia is characterized by formation of the abelson murine leukemia viral oncogene homolog/ breakpoint cluster region fusion gene, usually as a consequence of the Philadelphia translocation between chromosomes 9 and 22. Approximately 5%–10% of chronic myelocyctic leukemia patients show variant translocations involving other chromosomes in addition to chromosomes 9 and 22. We report a chronic myelocyctic leukemia case carrying variant Philadelphia translocation involving both chromosomes 9 and 22 as well as chromosomes 4. A detailed molecular cytogenetic characterization was performed by fluorescence in situ hybridization, which disclosed the presence of the5'breakpoint cluster region/3'abelson murine leukemia viral oncogene homolog 1 fusion gene was localized on the Philadelphia chromosome, whereas the 5'abelson murine leukemia viral oncogene homolog 1/3'breakpoint cluster region gene was not detected on the derivative (9) chromosome because 3'breakpoint cluster transferred onto partner chromosomes 4. Serial translocations or a single simultaneous event are alternative hypotheses proposed to justify the occurrence of these complex rearrangements.
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