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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Chromobox Protein Homolog 5
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism
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Disease Models, Animal
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Embryonic Stem Cells / cytology
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Embryonic Stem Cells / physiology*
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic
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HMGB3 Protein / genetics
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HMGB3 Protein / metabolism
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Humans
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Mice
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Mice, Inbred C57BL
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Neoplastic Stem Cells / cytology
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Neoplastic Stem Cells / physiology*
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Oligonucleotide Array Sequence Analysis
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Oncogene Proteins v-myb / genetics
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Oncogene Proteins v-myb / metabolism
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Transcription, Genetic*
Substances
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CBX5 protein, human
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CBX5 protein, mouse
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Chromosomal Proteins, Non-Histone
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HMGB3 Protein
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Oncogene Proteins v-myb
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Oncogene Proteins, Fusion
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Chromobox Protein Homolog 5
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Myeloid-Lymphoid Leukemia Protein