title: Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells.
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.
authors.affiliation: 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.
authors.forename: Tim C P
authors.initials: TC
authors.lastname: Somervaille
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Matheny
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Spencer
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwasaki
authors.forename: John L
authors.initials: JL
authors.lastname: Rinn
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Witten
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Shurtleff
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cleary
mesh_terms: 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
chemical_list: 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