Functional Crosstalk between Bmi1 and MLL/Hoxa9 Axis in Establishment of Normal Hematopoietic and Leukemic Stem Cells.

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^-l- cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and Hoxa9, readily transformed Bmi1^-l- cells. MLL-AF9 could not initiate leukemia in Bmi1^-l- Hoxa9^-l- 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^lnk4a/p19^ARF 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]