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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.

Authors :
Smith, Lan-Lan
Yeung, Jenny
Zeisig, Bernd B.
Popov, Nikolay
Huijbers, Ivo
Barnes, Josephine
Wilson, Amanda J.
Taskesen, Erdogan
Delwel, Ruud
Gil, Jesús
Van Lohuizen, Maarten
So, Chi Wai Eric
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]

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