Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells

Cell Stem Cell. 2009 Feb 6;4(2):129-40. doi: 10.1016/j.stem.2008.11.015.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Disease Models, Animal
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • HMGB3 Protein / genetics
  • HMGB3 Protein / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins v-myb / genetics
  • Oncogene Proteins v-myb / metabolism
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Transcription, Genetic*

Substances

  • Chromosomal Proteins, Non-Histone
  • HMGB3 Protein
  • Oncogene Proteins v-myb
  • Oncogene Proteins, Fusion
  • heterochromatin-specific nonhistone chromosomal protein HP-1
  • Myeloid-Lymphoid Leukemia Protein