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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1182-1192.
Prepublished online as a Blood First Edition Paper on November 1, 2007; DOI 10.1182/blood-2007-04-083600.
 Previous Article | Next Article 
Submitted April 10, 2007
Accepted October 28, 2007
CREB is a critical regulator of normal hematopoiesis and leukemogenesis
Jerry C Cheng, Kentaro Kinjo, Dejah Judelson, Jenny Chang, Winston S Wu, Ingrid Schmid, Deepa B Shankar, Noriyuki Kasahara, Renata Stripecke, Ravi Bhatia, Elliot M Landaw, and Kathleen M Sakamoto*
Division of Hematology/Oncology, Dept of Pediatrics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
Div. Hematology/Oncology, UCLA Flow Cytometry Core Facility, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
Discovery Biology, Jubilant Biosystems Ltd, Bangalore, India
Molecular Biology Institute, UCLA, Los Angeles, CA, United States
Department of Hematopoietic Stem Cell and Leukemia Biology, City of Hope, Duarte, CA, United States
Department of Biomathematics, UCLA, Los Angeles, CA, United States
Division of Biology, California Institute of Technology, Pasedena, CA, United States
* Corresponding author; email: kms{at}ucla.edu.
The cAMP-responsive element binding protein (CREB) is a 43kDa nuclear transcription factor that regulates cell growth, memory, and glucose homeostasis. We previously showed that CREB is amplified in myeloid leukemia blasts and is expressed at higher levels in leukemia stem cells from patients with myeloid leukemia. CREB transgenic mice develop myeloproliferative disease after one 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 knockdown 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 transplanted with bone marrow transduced with CREB shRNA had decreased committed progenitors compared to controls. 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.
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