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,
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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).
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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.
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    • "DEK is a nuclear protein, with both RNA and DNA binding properties, expressed in many tissues [5] [6]. This gene is implicated in a subset of AML carrying the t(6;9)(p23;q34) in which the DEK-CAN protein confers poor prognosis [7] [8]. CBL protooncogene product participates in signal transduction of hematopoietic cells [9]. "
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    ABSTRACT: Previous gene function analyses have indicated that HOXA9, DEK, CBL and CSF1R are aberrantly expressed in acute myeloid leukemia (AML). We analyzed the expression of these genes in a series of 41 adult patients with AML using quantitative real-time RT-PCR, and tested the association of the expression with the following hematologic and clinical parameters: age, FAB, immunophenotype and karyotype aberrations. A high proportion of the patients showed over- or underexpression of the analyzed genes. DEK was overexpressed in 98% of the cases, whereas CBL, CSF1R and HOXA9 were either overexpressed in 20%, 17% and 78% or underexpressed in 20%, 42% and 15% of the cases, respectively. Patients whose karyotype contained t(8;21)(q22;q22), showed lower relative expression of HOXA9 at a statistically significant level (p < 0.05). Bone marrow samples without expression of CD34 antigen were associated with either overexpression of DEK or HOXA9. Furthermore, an association was found between the AML-M2 subtype and lower expression of CBL, CSF1R or HOXA9, and between the AML-M5 subtype and CBL or CSF1R overexpression.
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