CREB is a critical regulator of normal hematopoiesis and leukemogenesis
CREB is a critical regulator of normal hematopoiesis and leukemogenesis
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DOI：
10.1182/blood-blood-2007-04-083600
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Sakamoto, Kathleen M.
中科院分区：
文献类型：
--
作者：
Cheng, Jerry C.;Kinjo, Kentaro;Sakamoto, Kathleen M.
CAMP反应元件结合蛋白(CREB)是一种43 kDa的核转录因子，调节细胞生长、记忆和葡萄糖稳态。我们之前的研究表明，CREB在髓系白血病原始细胞中扩增，并在髓系白血病患者的白血病干细胞中高水平表达。CREB转基因小鼠在1年后发展为骨髓增生性疾病，但不是白血病，这表明CREB有助于白血病的发生，但不是充分的。在这里，我们发现CREB在谱系阴性的造血干细胞(HSCs)中表达最高。为了了解CREB在造血祖细胞和白血病细胞中的作用，我们在体外和体内检测了RNA干扰(RNAi)下调CREB表达的效果。慢病毒CREB shRNAs转导原代HSCs或髓系白血病细胞后，干细胞增殖减少，细胞周期异常，CREB转录受抑。与对照组相比，接受CREB shRNA转导的骨髓移植的小鼠的承诺祖细胞减少。注射表达bcr-Abl野生型或T3151突变的Bcr-Abl野生型或T3151突变的Bcr-Abl野生型或T3151突变的Bcr/F3细胞后，CREB shRNA的生物发光成像显示，小鼠的白血病侵袭延迟，中位生存期延长。我们的结果表明，CREB对于正常的骨髓生成和白血病细胞的增殖是至关重要的。
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 T3151 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.