Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells.
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.
Somervaille
Tim C P
TC
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.
Matheny
Christina J
CJ
Spencer
Gary J
GJ
Iwasaki
Masayuki
M
Rinn
John L
JL
Witten
Daniela M
DM
Chang
Howard Y
HY
Shurtleff
Sheila A
SA
Downing
James R
JR
Cleary
Michael L
ML
D000818:Animals; D002478:Cells, Cultured; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D025765:HMGB3 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D020626:Oncogene Proteins v-myb / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
C000715594:CBX5 protein, human; C000715595:CBX5 protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D025765:HMGB3 Protein; D020626:Oncogene Proteins v-myb; D015514:Oncogene Proteins, Fusion; D000090266:Chromobox Protein Homolog 5; D051788:Myeloid-Lymphoid Leukemia Protein