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Hierarchical Maintenance of MLL Myeloid Leukemia Stem Cells Employs a Transcriptional Program Shared with Embryonic Rather Than Adult Stem Cells
Tim C.P. Somervaille1,4,Christina J. Matheny1,Gary J. Spencer4,Masayuki Iwasaki1,John L. Rinn2,Daniela M. Witten3,Howard Y. Chang2,Sheila A. Shurtleff5,James R. Downing5andMichael L. Cleary1,,
1 Department of Pathology, Stanford University, Stanford, CA 94305, USA
2 Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA
3 Department of Statistics, Stanford University, Stanford, CA 94305, USA
4 Cancer Research UK Leukaemia Biology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, UK
5 Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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.
