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Genetic control of hematopoietic stem cell biology and leukemogenesis



Genetic control of hematopoietic stem cell biology and leukemogenesis



Blood 102(11): 332a, November 16



This work seeks to identify genes which regulate hematopoietic stem cell expansion and differentiation. Retroviral gene transfer into human cord blood CD34+ cells was used to examine the effects of candidate gene over-expression in tissue culture and in engrafted immunocompromised NOD/SCID mice. We demonstrated that activation of ras signaling by over-expression of mutant N-ras (N-rasm) induced hyperproliferation of myeloid progenitor cells at the expense of lymphoid and erythroid differentiation. In vitro this hyperproliferation was associated with accelerated maturation of myeloid cells and the depletion of hematopoietic progenitor cells (CFU-GM). Increased engraftment of CD34+ cells and myeloid hyperproliferation at the expense of other lineages was also seen in NOD/SCID mice injected with N-rasm-transduced CD34+ cells. Over-expression of myc in CD34+ cells in vitro inhibited N-rasm-induced myeloid proliferation and differentiation as well as the depletion of hematopoietic progenitor cells. Transcription profiling of N-rasm-induced differentiation was performed in K562 and U937 cells with and without N-rasm. Verified by RT-PCR, this allowed the identification of putative mediators of N-rasm-induced differentiation. In this analysis 82 genes were differentially expressed in these cells. N-rasm over-expression was associated with up-regulation of IRF-1 and p21CIP1/WAF1. IRF-1 is a transcriptional activator of p21 and has been shown to be associated with induction of myeloid differentiation. IRF-1 has not previously been shown to be a ras responsive gene. However, IRF-1 is located in the 5q deletion that is common in AML. Our results have shown that inactivation of this IRF-1 tumour suppressive pathway appears to be important in N-rasm associated myeloid leukemogenesis. RNA interference is being used to suppress IRF-1 and p21CIP1/WAF1 in human hematopoietic stem cells.

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Accession: 034981909

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