Dev. Cell:揭示巨核細胞增大秘密

耶魯大學研究人員發現巨核細胞(megakaryocyte)---一種產生癒合傷口的血小板的巨大細胞---如何能夠生長至其他血細胞的10至15倍大。相關研究結果將於2012年3月13日發表在《細胞》子刊Developmental Cell期刊上，有助於人們理解這種過程發生故障如何可能導致一種類型白血病，即巨核細胞白血病(megakaryoblastic leukemia)。

「這些巨核細胞不能生長可能是導致巨核細胞白血病形成的初始觸發器」，論文通訊作者、耶魯大學癌症中心研究員、耶魯大學幹細胞中心副主任與實驗室醫學、細胞生物學和病理學教授Diane Krause說。

巨核細胞生長如此大是因為細胞內DNA複製很多次，但是沒有發生細胞分裂，這一過程被稱作核內有絲分裂(endomitosis)。一個成巨核細胞在它最終變成生物「超新星(supernova)」之前能夠容納120多套細胞核DNA，而一旦變成之後，它就經歷深刻變化而分裂成正常血液凝固所必需的上千個血小板。

耶魯大學博士後研究助理Yuan Gao領導的一個研究小組發現兩種被稱作鳥苷酸交換因子(guanine exchange factor, GEF-H1)的蛋白能夠抑制核內有絲分裂。他們發現若沒有GEF-H1，細胞核DNA不能夠從2個細胞內核變成4個。隨後，除非另一個因子ECT2表達水平下降，細胞內細胞核DNA分裂不可能發生。

研究人員發現一個與惡性白血病相關的基因MKL1似乎也是促進正常巨核細胞成熟所必需的，他們對此感到吃驚。Krause實驗室如今正在研究MKL1基因發生突變是否可以維持高水平GEF-H1從而使得巨核細胞不可能經歷核內有絲分裂，從而為白血病產生作好鋪墊。

「功能性血小板是正常血液凝固所必需的，而這些研究發現揭示功能性血小板形成的另一個重要性步驟。不過它們也提供關於是什麼可能發生偏差而導致正常巨核細胞轉變成惡性白血病細胞的線索。」 (生物谷：towersimper編譯)

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.

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.