The translocation (6;9)(p23;q34) shows consistent rearrangement of 2 genes and defines a myeloproliferative disorder with specific clinical features

Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands.
Blood (Impact Factor: 10.45). 07/1992; 79(11):2990-7.
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Translocation (6;9)(p23;q34) is a cytogenetic aberration that can be found in specific subtypes of both acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). This translocation is associated with an unfavourable prognosis. Recently, the genes involved in the t(6;9) were isolated and characterized. Breakpoints in both the dek gene on chromosome 6 and the can gene on chromosome 9 appear to occur in defined regions, which allows us to diagnose this type of leukemia at the molecular level. Moreover, because of the translocation a chimeric dek-can mRNA is formed which, as we show here, is an additional target for diagnosis via cDNA-preparation and the polymerase chain reaction (PCR). We studied 17 patients whose blood cells and/or bone marrow cells showed a t(6;9) with karyotypic analysis. Fourteen patients suffered from AML, one patient had a refractory anemia with excess of blasts in transformation (RAEBt), one patient had an acute myelofibrosis (AMF), and one patient a chronic myeloid leukemia (CML). In nine cases studies at the DNA and RNA levels were possible while in seven cases only the DNA could be analyzed. In one case only RNA was available. Conventional Southern blot analysis showed the presence of rearrangements of both the dek gene and the can gene. In both genes, breakpoints cluster in one intron in the patients investigated. The presence of a consistent chimeric dek-can product after cDNA preparation followed by the PCR was demonstrated. We conclude from our data that the t(6;9) is found in myeloproliferative disorders with typical clinical characteristics. This translocation results in highly consistent abnormalities at the molecular level.

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Available from: Marieke von Lindern, Oct 02, 2015
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    • "While the majority (81%) of our patients had AML, the translocation was also seen in MDS and CML. The t(6;9) is associated with FAB-M2 or M4 subtypes in 61e90% of patients [1] [2]. Varying degrees of dysplasia, usually trilineage, have been reported in 67e100% of patients [1] [9] [18]. "
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    ABSTRACT: Among patients with acute myeloid leukemia (AML), the t(6;9) (p22;q34) is a rare but defined subset with a poor prognosis. We report 16 patients with the t(6;9), of whom 13 had AML, 2 had myelodysplastic syndrome (MDS), and 1 had chronic myeloid leukemia in myeloid blast crisis (CML-BC). All except for one were evaluated at diagnosis. The median age was 34.5 (range: 7-62 years), with 12 adults and 12 males. Trilineage dysplasia was present in 13 (81%). Marrow basophilia was seen in only two patients, one of whom had CML-BC. HLA-DR was positive in all 12 patients assessed, CD33 in 11, CD13 in 10, and CD34 in seven. Four patients had one other abnormality apart from the t(6;9). These were the t(9;22) in the patient with CML and deletion 9q, addition 13q, and an isochromosome 8q in the other three patients. There were no complex karyotypes. Fms-related tyrosine kinase 3--internal tandem duplication (FLT3-ITD) mutations were seen in seven of 13 patients. Follow-up details were available for six patients. Three received palliative care, and follow-up details were not available for the other seven. The response to chemotherapy was poor in the remaining patients. The only patients who survived were three out of the four who had allogeneic hematopoietic stem cell transplantation (HSCT).
    Cancer genetics and cytogenetics 12/2010; 203(2):297-302. DOI:10.1016/j.cancergencyto.2010.08.012 · 1.93 Impact Factor
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    • "The similarities of motif organizations in human and fly DEKs suggest that DEKs serve as a class of histone chaperone. Thus, it is feasible that this hDEK function is compromised by its fusion with CAN in AML patients (Fig. 7A; Soekarman et al. 1992; von Lindern et al. 1992). "
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    ABSTRACT: Chromatin reorganization is essential for transcriptional control by sequence-specific transcription factors. However, the molecular link between transcriptional control and chromatin reconfiguration remains unclear. By colocalization of the nuclear ecdysone receptor (EcR) on the ecdysone-induced puff in the salivary gland, Drosophila DEK (dDEK) was genetically identified as a coactivator of EcR in both insect cells and intact flies. Biochemical purification and characterization of the complexes containing fly and human DEKs revealed that DEKs serve as histone chaperones via phosphorylation by forming complexes with casein kinase 2. Consistent with the preferential association of the DEK complex with histones enriched in active epigenetic marks, dDEK facilitated H3.3 assembly during puff formation. In some human myeloid leukemia patients, DEK was fused to CAN by chromosomal translocation. This mutation significantly reduced formation of the DEK complex, which is required for histone chaperone activity. Thus, the present study suggests that at least one histone chaperone can be categorized as a type of transcriptional coactivator for nuclear receptors.
    Genes & development 01/2010; 24(2):159-70. DOI:10.1101/gad.1857410 · 10.80 Impact Factor
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    • "The following considerations are pertinent to this issue: (a) the t(1;7) was found only at the time of leukaemic evolution of primary MDS in patient 3, who featured a normal karyotype throughout the preleukaemic phase, suggesting that the acquisition of this aberration may be closely associated with the development of leukaemia; (b) the association with classic t(6;9) is not surprising considering that one patient has previously been reported with the 6;9 translocation associated with a 7q¹ chromosome and that approximately a third of the previously reported t(6;9) cases had additional changes, especially at relapse (Soekarman et al, 1992). It is also noteworthy that the t(6;9) has previously been described in AML and in a spectrum of myeloid stem cell disorders including MDS, in association with environmental exposure to myelotoxic agents (Fonatsch et al, 1987; Cuneo et al, 1989; Soekarman et al, 1992); (c) a 1p;7q translocation has previously been observed in association with well-known primary chromosome defects (i.e. the 8;21 translocation, the inv(16), etc.); (d) the presence of trisomy 8 as a secondary change is very common in myeloid neoplasias (Cuneo et al, 1998) and does not bear any evident clinico-biological impact apart from that dictated by the primary chromosome change. It is reasonable to suggest that this newly described translocation may be a primary cytogenetic aberration in some cases and that it may cooperate with other primary "
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    ABSTRACT: Studies of large numbers of patients have enabled the identification of relatively infrequent chromosome changes, such as inv(3)(q21;q26), t(6;9)(p23;q34) and t(8;16)(p11;p11), whose clinico-biological significance is gradually becoming clearer. Translocations involving chromosomes 1 and 7 are relatively rare in myeloid neoplasias, being found in far less than 1% of cases; the rearrangement that occurs most frequently consists of an unbalanced translocation [t(1;7)(p11; p11)], resulting in complete loss of 7q, associated with therapy-related or environmentally-induced high-risk myelodysplasia. We recently observed three cases of acute myeloid leukaemia (AML) with a previously unreported balanced translocation t(1;7) (p36;q34). Case 1 underwent autologous bone marrow transplantation and remains alive in CR; cases 2 and 3 relapsed after 10 and 4 months, respectively. The response to chemotherapy observed in our cases suggests that variable clinical features might be present in the broad cytogenetic category usually referred to as '7q abnormalities' and contributes to an interesting previous observation of prolonged disease-free survival in a subset of AMLs with 7q- as the isolated chromosome change.
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