Decitabine Maintains Hematopoietic Precursor Self-Renewal by Preventing Repression of Stem Cell Genes by a Differentiation-Inducing Stimulus
Open Access
- 1 June 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 9 (6), 1536-1543
- https://doi.org/10.1158/1535-7163.mct-10-0191
Abstract
The cytosine analogue decitabine alters hematopoietic differentiation. For example, decitabine treatment increases self-renewal of normal hematopoietic stem cells. The mechanisms underlying decitabine-induced shifts in differentiation are poorly understood, but likely relate to the ability of decitabine to deplete the chromatin-modifying enzyme DNA methyltransferase 1 (DNMT1), which plays a central role in transcription repression. HOXB4 is a transcription factor that promotes hematopoietic stem cell self-renewal. In hematopoietic precursors induced to differentiate by the lineage-specifying transcription factor Pu.1 or by the cytokine granulocyte-colony stimulating factor, there is rapid repression of HOXB4 and other stem cell genes. Depletion of DNMT1 using shRNA or decitabine prevents HOXB4 repression by Pu.1 or granulocyte-colony stimulating factor and maintains hematopoietic precursor self-renewal. In contrast, depletion of DNMT1 by decitabine 6 hours after the differentiation stimulus, that is, after repression of HOXB4 has occurred, augments differentiation. Therefore, DNMT1 is required for the early repression of stem cell genes, which occurs in response to a differentiation stimulus, providing a mechanistic explanation for the observation that decitabine can maintain or increase hematopoietic stem cell self-renewal in the presence of a differentiation stimulus. Using decitabine to deplete DNMT1 after this early repression phase does not impair progressive differentiation. Mol Cancer Ther; 9(6); 1536–43. ©2010 AACR.Keywords
This publication has 33 references indexed in Scilit:
- DNA Methyltransferase 1 Is Essential for and Uniquely Regulates Hematopoietic Stem and Progenitor CellsCell Stem Cell, 2009
- Differentiation therapy of leukemia: 3 decades of developmentBlood, 2009
- The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylationNature Genetics, 2008
- Clinical effectiveness of decitabine in severe sickle cell diseaseBritish Journal of Haematology, 2008
- Chromatin Challenges during DNA Replication: A Systems RepresentationMolecular Biology of the Cell, 2008
- Dynamics of Dnmt1 interaction with the replication machinery and its role in postreplicative maintenance of DNA methylationNucleic Acids Research, 2007
- Expansion of human umbilical cord blood SCID-repopulating cells using chromatin-modifying agentsExperimental Hematology, 2006
- 5-Aza-Deoxycytidine Induces Selective Degradation of DNA Methyltransferase 1 by a Proteasomal Pathway That Requires the KEN Box, Bromo-Adjacent Homology Domain, and Nuclear Localization SignalMolecular and Cellular Biology, 2005
- Histone deacetylase activity is required for embryonic stem cell differentiationgenesis, 2003
- Purification of human DNA (cytosine‐5‐)‐methyltransferaseJournal of Cellular Biochemistry, 1985