Molecular interactions involved in HOXB4-induced activation of HSC self-renewal
Molecular interactions involved in HOXB4-induced activation of HSC self-renewal
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DOI：
10.1182/blood-2004-04-1653
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发表时间：
2004-10-15
期刊：
影响因子：
20.3
通讯作者：
Sauvageau, G
中科院分区：
文献类型：
--
作者：
Beslu, N;Krosl, J;Sauvageau, G
HOXB4 过表达可诱导造血干细胞 (HSC) 独特的体内和体外扩增，而不会引起白血病。关于 HOXB4 诱导 HSC 自我更新的分子基础知之甚少。我们现在报道了原代骨髓（BM）细胞的体外增殖和体内扩增能力，这些细胞被设计为过表达选定的HOXB4点突变体，这些突变体缺乏直接结合DNA（HOXB4（A））的能力，或在DNA结合中与PBX家族成员（HOXB4（W-->G））合作的能力。 DNA结合无能的HOXB4突变体未能增强转导的BM群体的体外增殖活性和体内HSC扩增。相比之下，HOXB4(W-G)突变体赋予转导的BM群体显着的体外增殖优势，并显着增强其体内再生潜力。我们还证明了 HOXB4 蛋白水平与原代 BM 细胞的体外增殖能力之间的相关性。因此，我们的观察结果表明，HOXB4 诱导 HSC 扩增的能力是 DNA 结合依赖性的，不需要直接的 HOW PBX 相互作用，并为鉴定参与 HSC 扩增的 HOXB4 依赖性靶标奠定了基础。 (C) 2004 年，美国血液学会。
HOXB4 overexpression induces unique in vivo and in vitro expansion of hemopoietic stem cells (HSCs) without causing leukemia. Very little is known about the molecular basis underlying HOXB4-induced HSC self-renewal. We now report the in vitro proliferation and in vivo expansion capacity of primary bone marrow (BM) cells engineered to overexpress selected HOXB4 point mutants lacking either the capacity to directly bind DNA (HOXB4(A)), or to cooperate with members of the PBX family (HOXB4(W-->G)) in DNA binding. The DNA binding-incompetent HOXB4 mutant failed to enhance the proliferation activity of transduced BM populations in vitro and HSC expansion in vivo. In contrast, the HOXB4(W-G) mutant conferred a pronounced in vitro proliferation advantage to the transduced BM populations, and dramatically enhanced their in vivo regenerative potential. We also demonstrate a correlation between HOXB4 protein levels and in vitro proliferative capacity of primary BM cells. Our observations thus suggest that the capacity of HOXB4 to induce HSC expansions is DNA-binding dependent and does not require direct HOW PBX interaction, and sets the stage for identifying HOXB4-dependent targets involved in HSC expansion. (C) 2004 by The American Society of Hematology.