Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10.

Blood
Kevin OakleyYang Du

Abstract

Acquisition of self-renewal capability by myeloid progenitors to become leukemic stem cells during myeloid leukemia development is poorly understood. Here, we show that Setbp1 overexpression efficiently confers self-renewal capability to myeloid progenitors in vitro, causing their immortalization in the presence of stem cell factor and IL-3. Self-renewal after immortalization requires continuous Setbp1 expression. We also found that Hoxa9 and Hoxa10 mRNA are present at dramatically higher levels in Setbp1-immortalized cells compared with other immortalized cells, and are induced shortly after Setbp1 expression in primary myeloid progenitors. Suppression of either gene in Setbp1-immortalized cells drastically reduces their colony-forming capability. Interestingly, Setbp1 protein associates with Hoxa9 and Hoxa10 promoters in chromatin immunoprecipitation assays in these cells, suggesting that both are direct transcriptional targets of Setbp1. Setbp1 also promotes self-renewal of myeloid progenitors in vivo as its coexpression with BCR/ABL transforms primary mouse myeloid progenitors, generating aggressive leukemias in recipient mice resembling chronic myelogenous leukemia (CML) myeloid blast crisis. Increased SETBP1 mRNA levels w...Continue Reading

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Citations

Dec 25, 2012·Current Hematologic Malignancy Reports·Ross Kinstrie, Mhairi Copland
Dec 12, 2012·Nature Genetics·Rocco PiazzaCarlo Gambacorti-Passerini
Jul 9, 2013·Nature Genetics·Hideki MakishimaJaroslaw P Maciejewski
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May 21, 2020·Cancers·Kanae YumimotoKeiichi I Nakayama

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