MLL髓系白血病干细胞的分层维持采用了一种与胚胎干细胞而非成体干细胞共有的转录程序。
Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells.
作者信息
Somervaille Tim C P, Matheny Christina J, Spencer Gary J, Iwasaki Masayuki, Rinn John L, Witten Daniela M, Chang Howard Y, Shurtleff Sheila A, Downing James R, Cleary Michael L
机构信息
Department of Pathology, Stanford University, Stanford, CA 94305, USA; Cancer Research UK Leukaemia Biology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
出版信息
Cell Stem Cell. 2009 Feb 6;4(2):129-40. doi: 10.1016/j.stem.2008.11.015.
The genetic programs that promote retention of self-renewing leukemia stem cells (LSCs) at the apex of cellular hierarchies in acute myeloid leukemia (AML) are not known. In a mouse model of human AML, LSCs exhibit variable frequencies that correlate with the initiating MLL oncogene and are maintained in a self-renewing state by a transcriptional subprogram more akin to that of embryonic stem cells (ESCs) than to that of adult stem cells. The transcription/chromatin regulatory factors Myb, Hmgb3, and Cbx5 are critical components of the program and suffice for Hoxa/Meis-independent immortalization of myeloid progenitors when coexpressed, establishing the cooperative and essential role of an ESC-like LSC maintenance program ancillary to the leukemia-initiating MLL/Hox/Meis program. Enriched expression of LSC maintenance and ESC-like program genes in normal myeloid progenitors and poor-prognosis human malignancies links the frequency of aberrantly self-renewing progenitor-like cancer stem cells (CSCs) to prognosis in human cancer.
促进急性髓系白血病（AML）细胞层级顶端自我更新白血病干细胞（LSC）留存的基因程序尚不清楚。在人类AML小鼠模型中，LSC表现出不同频率，这些频率与起始MLL癌基因相关，并通过一个转录子程序维持在自我更新状态，该子程序更类似于胚胎干细胞（ESC）而非成体干细胞。转录/染色质调节因子Myb、Hmgb3和Cbx5是该程序的关键组成部分，当共同表达时，足以使髓系祖细胞在不依赖Hoxa/Meis的情况下永生化，确立了白血病起始MLL/Hox/Meis程序辅助的类ESC的LSC维持程序的协同和重要作用。正常髓系祖细胞和预后不良的人类恶性肿瘤中LSC维持和类ESC程序基因的富集表达，将异常自我更新的祖细胞样癌症干细胞（CSC）频率与人类癌症预后联系起来。
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