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Functional Crosstalk between Bmi1 and MLL/Hoxa9 Axis in Establishment of Normal Hematopoietic and Leukemic Stem Cells.
Functional Crosstalk between Bmi1 and MLL/Hoxa9 Axis in Establishment of Normal Hematopoietic and Leukemic Stem Cells.
- Source :
- Cell Stem Cell; 6/3/2011, Vol. 8 Issue 6, p649-662, 14p
- Publication Year :
- 2011
-
Abstract
- Bmi1 is required for efficient self-renewal of hematopoietic stem cells (HSC5) and leukemic stem cells (LSCs). In this study, we investigated whether leukemia-associated fusion proteins, which differ in their ability to activate Hox expression, could initiate leukemia in the absence of Bmil. AML1 -ETO and PLZF-RARα, which do not activate Hox, triggered senescence in Bmi1<superscript>-l-</superscript> cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and Hoxa9, readily transformed Bmi1<superscript>-l-</superscript> cells. MLL-AF9 could not initiate leukemia in Bmi1<superscript>-l-</superscript> Hoxa9<superscript>-l-</superscript> mice, which have further compromised HSC functions. But either gene could restore the ability of MLL-AF9 to establish LSCs in the double null background. As reported for Bmi1, Hoxa9 regulates expression of p16<superscript>lnk4a</superscript>/p19<superscript>ARF</superscript> locus and could overcome senescence induced by AML1 -ETO. Together, these results reveal an important functional interplay between MLL/Hox and Bmil in regulating cellular senescence for LSC development, suggesting that a synergistic targeting of both molecules is required to eradicate a broader spectrum of LSCs. [ABSTRACT FROM AUTHOR]
- Subjects :
- HEMATOPOIETIC stem cells
CELLULAR aging
LEUKEMIA
LABORATORY mice
STEM cell research
Subjects
Details
- Language :
- English
- ISSN :
- 19345909
- Volume :
- 8
- Issue :
- 6
- Database :
- Supplemental Index
- Journal :
- Cell Stem Cell
- Publication Type :
- Academic Journal
- Accession number :
- 61331375
- Full Text :
- https://doi.org/10.1016/j.stem.2011.05.004