耶鲁大学研究人员发现巨核细胞(megakaryocyte)---一种产生愈合伤口的血小板的巨大细胞---如何能够生长至其他血细胞的10至15倍大。相关研究结果将于2012年3月13日发表在《细胞》子刊Developmental Cell期刊上，有助于人们理解这种过程发生故障如何可能导致一种类型白血病，即巨核细胞白血病(megakaryoblastic leukemia)。
“这些巨核细胞不能生长可能是导致巨核细胞白血病形成的初始触发器”，论文通讯作者、耶鲁大学癌症中心研究员、耶鲁大学干细胞中心副主任与实验室医学、细胞生物学和病理学教授Diane Krause说。
巨核细胞生长如此大是因为细胞内DNA复制很多次，但是没有发生细胞分裂，这一过程被称作核内有丝分裂(endomitosis)。一个成巨核细胞在它最终变成生物“超新星(supernova)”之前能够容纳120多套细胞核DNA，而一旦变成之后，它就经历深刻变化而分裂成正常血液凝固所必需的上千个血小板。
耶鲁大学博士后研究助理Yuan Gao领导的一个研究小组发现两种被称作鸟苷酸交换因子(guanine exchange factor, GEF-H1)的蛋白能够抑制核内有丝分裂。他们发现若没有GEF-H1，细胞核DNA不能够从2个细胞内核变成4个。随后，除非另一个因子ECT2表达水平下降，细胞内细胞核DNA分裂不可能发生。
研究人员发现一个与恶性白血病相关的基因MKL1似乎也是促进正常巨核细胞成熟所必需的，他们对此感到吃惊。Krause实验室如今正在研究MKL1基因发生突变是否可以维持高水平GEF-H1从而使得巨核细胞不可能经历核内有丝分裂，从而为白血病产生作好铺垫。
“功能性血小板是正常血液凝固所必需的，而这些研究发现揭示功能性血小板形成的另一个重要性步骤。不过它们也提供关于是什么可能发生偏差而导致正常巨核细胞转变成恶性白血病细胞的线索。” (生物谷：towersimper编译)
doi:10.1016/j.devcel.2011.12.019
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Role of RhoA-Specific Guanine Exchange Factors in Regulation of Endomitosis in Megakaryocytes
Yuan Gao, Elenoe Smith, Elmer Ker, Phil Campbell, Ee-chun Cheng, Siying Zou, Sharon Lin, Lin Wang, Stephanie Halene, Diane S. Krause
Polyploidization can precede the development of aneuploidy in cancer. Polyploidization in megakaryocytes (Mks), in contrast, is a highly controlled developmental process critical for efficient platelet production via unknown mechanisms. Using primary cells, we demonstrate that the guanine exchange factors GEF-H1 and ECT2, which are often overexpressed in cancer and are essential for RhoA activation during cytokinesis, must be downregulated for Mk polyploidization. The first (2N–4N) endomitotic cycle requires GEF-H1 downregulation, whereas subsequent cycles (>4N) require ECT2 downregulation. Exogenous expression of both GEF-H1 and ECT2 prevents endomitosis, resulting in proliferation of 2N Mks. Furthermore, we have shown that the mechanism by which polyploidization is prevented in Mks lacking Mkl1, which is mutated in megakaryocytic leukemia, is via elevated GEF-H1 expression; shRNA-mediated GEF-H1 knockdown alone rescues this ploidy defect. These mechanistic insights enhance our understanding of normal versus malignant megakaryocytopoiesis, as well as aberrant mitosis in aneuploid cancers.
doi:10.1016/j.devcel.2012.02.010
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GEFs on the RhoAd to a Colossal Nucleus
Ramesh A. Shivdasani
Cytokinesis in normal cell division requires RhoA-regulated actomyosin contraction of the cleavage furrow; this process is aborted in megakaryocyte endomitosis, leading to polyploidy. In this issue of Developmental Cell, Gao et al., 2012 trace the basis of endomitosis to sequential downregulation of guanine nucleotide exchange factors GEF-H1 and ECT2.
