Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells.
Cell Stem Cell, 2009/2/06;4(2):129-40.
Somervaille TC[1], Matheny CJ, Spencer GJ, Iwasaki M, Rinn JL, Witten DM, Chang HY, Shurtleff SA, Downing JR, Cleary ML
Affiliations
PMID: 19200802DOI: 10.1016/j.stem.2008.11.015
Impact factor: 25.269
Abstract
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.
MeSH terms
Animals; Cells, Cultured; Chromobox Protein Homolog 5; Chromosomal Proteins, Non-Histone; Disease Models, Animal; Embryonic Stem Cells; Gene Expression Profiling; Gene Expression Regulation, Leukemic; HMGB3 Protein; Humans; Mice; Mice, Inbred C57BL; Myeloid-Lymphoid Leukemia Protein; Neoplastic Stem Cells; Oligonucleotide Array Sequence Analysis; Oncogene Proteins v-myb; Oncogene Proteins, Fusion; Transcription, Genetic
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