[PDF][PDF] Functional crosstalk between Bmi1 and MLL/Hoxa9 axis in establishment of normal hematopoietic and leukemic stem cells

LL Smith, J Yeung, BB Zeisig, N Popov, I Huijbers… - Cell stem cell, 2011 - cell.com
LL Smith, J Yeung, BB Zeisig, N Popov, I Huijbers, J Barnes, AJ Wilson, E Taskesen
Cell stem cell, 2011cell.com
Bmi1 is required for efficient self-renewal of hematopoietic stem cells (HSCs) 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 Bmi1. AML1-ETO and PLZF-RARα, which do not activate Hox, triggered
senescence in Bmi1−/− cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and
Hoxa9, readily transformed Bmi1−/− cells. MLL-AF9 could not initiate leukemia in Bmi1 …
Summary
Bmi1 is required for efficient self-renewal of hematopoietic stem cells (HSCs) 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 Bmi1. AML1-ETO and PLZF-RARα, which do not activate Hox, triggered senescence in Bmi1−/− cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and Hoxa9, readily transformed Bmi1−/− cells. MLL-AF9 could not initiate leukemia in Bmi1−/−Hoxa9−/− 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 p16Ink4a/p19ARF locus and could overcome senescence induced by AML1-ETO. Together, these results reveal an important functional interplay between MLL/Hox and Bmi1 in regulating cellular senescence for LSC development, suggesting that a synergistic targeting of both molecules is required to eradicate a broader spectrum of LSCs.
cell.com