Acute myeloid leukemia with t(7;21)(q11.2;q22) expresses a novel, reversed-sequence RUNX1-DTX2 chimera.
ABSTRACT The RUNX1 gene is frequently rearranged in acute leukemia. We cloned a novel RUNX1 chimeric gene generated by t(7;21)(q11.2;q22) in a patient with acute myeloid leukemia. 3'-rapid amplification of cDNA ends analysis showed a tail-to-tail fusion between RUNX1 on 21q22 and DTX2 on 7q11.2, with an insertion of short complementary sequence from UPK3B adjacent to DTX2. DTX2 encodes a putative E3-ubiquitin ligase with no known biological function. There are two possible functions of RUNX1-reversed UPK3B-DTX2: one from aberrant RUNX1 chimeric protein and the other from the reversed sequence of DTX2. The predicted aberrant protein expressed under the RUNX1 promoter was highly structurally similar to RUNX1a. In a reporter assay, the aberrant protein inhibited the trans-activation function of RUNX1 in a dominant-negative manner, similar to RUNX1a. In contrast, the DTX2 reversed sequence may degrade wild-type DTX2 transcript or suppress its translation. In conclusion, we identified a novel fusion RUNX1 partner, DTX2, which chimerize in a reverse direction. This is the first example of RUNX1 chimera in an opposing direction generated by chromosomal translocation in leukemia. In addition to the aberrantly truncated RUNX1 protein, the DTX2 antisense sequence may play some role in the development of leukemia carrying the t(7;21) translocation.
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ABSTRACT: Hematopoietic development requires coordinated actions from a variety of transcription factors. The core binding factor (CBF), consisting of a Runx protein and the CBFbeta protein, is a transcription factor complex that is essential for emergence of the hematopoietic stem cell (HSC) from an endothelial cell stage. The hematopoietic defects observed in either Runx1 or CBFbeta knockout mice underscore the necessity of this complex for definitive hematopoiesis. Despite the requirement for CBF in establishing definitive hematopoiesis, Runx1 loss has minimal impact on maintaining the HSC state postnatally, while CBFbeta may continue to be essential. Lineage commitment, on the other hand, is significantly affected upon CBF loss in the adult, indicating a primary role for this complex in modulating differentiation. Given the impact of normal CBF function in the hematopoietic system, the severe consequences of disrupting CBF activity, either through point mutations or generation of fusion genes, are obvious. The physiologic role of CBF in differentiation is subverted to an active process of self-renewal maintenance by the genetic aberrations, through several possible mechanisms, contributing to the development of hematopoietic malignancies including myelodysplastic syndrome and leukemia. The major impact of CBF on the hematopoietic system in both development and disease highlights the need for understanding the intricate functions of this complex and reiterate the necessity of continued efforts to identify potential points of therapeutic intervention for CBF-related diseases.Journal of Cellular Physiology 10/2009; 222(1):50-6. · 4.22 Impact Factor
- Leukemia 09/2003; 17(8):1665-6. · 10.16 Impact Factor
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ABSTRACT: The RUNX gene family includes three evolutionarily conserved genes (RUNX1, RUNX2 and RUNX3) encoding transcription factors involved in cell lineage differentiation during development and various forms of cancer. The RUNX1 gene, located in chromosome 21q22, is crucial for the establishment of definite hematopoiesis and the generation of hematopoietic stem cells in the embryo. It contains a "Runt homology domain" (RHD) and a transactivation domain. RUNX1 can act as activator or repressor of target gene expression depending upon the large number of transcription factors, coactivators and corepressors that interact with it. Three modes of leukemogenesis due to acquired alterations of the RUNX1 gene have been recognized: point mutations, amplification and translocations. Some translocations have been shown to be recurrent whereas others have been only reported in a few cases or in a sole case. At present, 32 partner chromosomes have been described but the partner gene has solely been identified in 17 translocations at the molecular level. Most of the translocations involving RUNX1 lead to the formation of a fusion transcript made of the 5' region of RUNX1, including the RHD, fused to the 3' region of a partner gene, with the exception of RUNX1-ETV6 in which the 3' sequences of RUNX1, including the RHD, are fused to the 5' region of ETV6, including its promotor. Three RUNX1 translocations (retaining RHD) that are fused out of frame to partner genes are also known. All the translocations that retain RHD but remove the transcription activation domain have a leukemogenic effect by acting as dominant negative inhibitors of wild-type RUNX1 in transcription activation.Anticancer research 05/2009; 29(4):1031-7. · 1.71 Impact Factor