CREB is a critical regulator of normal hematopoiesis and leukemogenesis
The cAMP-responsive element binding protein (CREB) is a 43-kDa nuclear transcription factor that regulates cell growth, memory, and glucose homeostasis. We showed previously that CREB is amplified in myeloid leukemia blasts and expressed at higher levels in leukemia stem cells from patients with myeloid leukemia. CREB transgenic mice develop myeloproliferative disease after 1 year, but not leukemia, suggesting that CREB contributes to but is not sufficient for leukemogenesis. Here, we show that CREB is most highly expressed in lineage negative hematopoietic stem cells (HSCs). To understand the role of CREB in hematopoietic progenitors and leukemia cells, we examined the effects of RNA interference (RNAi) to knock down CREB expression in vitro and in vivo. Transduction of primary HSCs or myeloid leukemia cells with lentiviral CREB shRNAs resulted in decreased proliferation of stem cells, cell- cycle abnormalities, and inhibition of CREB transcription. Mice that received transplants of bone marrow transduced with CREB shRNA had decreased committed progenitors compared with control mice. Mice injected with Ba/F3 cells expressing either Bcr-Abl wild-type or T315I mutation with CREB shRNA had delayed leukemic infiltration by bioluminescence imaging and prolonged median survival. Our results suggest that CREB is critical for normal myelopoiesis and leukemia cell proliferation.
© 2008 American Society of Hematology. Submitted April 9, 2007; accepted October 28, 2007. Prepublished online as Blood First Edition Paper, November 1, 2007 DOI: 10.1182/blood-2007-04-083600 This work was supported in part by National Institutes of Health grants HL75826 (K.M.S.), HL83077 (K.M.S.), CA16042 (I.S. and E.L.), AI28697 (I.S.), 2P30-DK041301 (N.K.), and F32-HL085013 (J.C.); American Cancer Society grant RSG-99-081-01-LIB (K.M.S.); and Department of Defense grant CM050077 (K.M.S.). K.M.S. is a scholar of the Leukemia and Lymphoma Society. Contribution: J.C. wrote the manuscript and designed and performed experiments. K.K., W.S.W., D.J., and J.C. performed experiments. I.S. helped analyze data, supervised experiments, and edited the manuscript. D.B.S. helped design experiments. N.K. contributed reagents. R.B. edited the manuscript and consulted on project. E.M.L. performed statistical analysis and wrote the manuscript. K.M.S. supervised the research, designed experiments, contributed to analysis, and edited the manuscript. Conflict-of-interest disclosure: The authors declare no competing financial interests. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. The online version of this article contains a data supplement.
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