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.
Cheng
Jerry C
JC
Division of Hematology/Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories and Mattel Children's Hospital, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095-1752, USA.
Kinjo
Kentaro
K
Judelson
Dejah R
DR
Chang
Jenny
J
Wu
Winston S
WS
Schmid
Ingrid
I
Shankar
Deepa B
DB
Kasahara
Noriyuki
N
Stripecke
Renata
R
Bhatia
Ravi
R
Landaw
Elliot M
EM
Sakamoto
Kathleen M
KM
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference; D015996:Survival Rate
D017362:Cyclic AMP Response Element-Binding Protein; D019925:Cyclin A; D019938:Cyclin D1