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 (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/p19ARFlocus 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.
|Persistent URL||dx.doi.org/10.1016/j.stem.2011.05.004, hdl.handle.net/1765/26118|
Smith, L.L., Yeung, J., Zeisig, B.B., Popov, N., Huijbers, I., Barnes, J., … So, C.W.E.. (2011). Functional crosstalk between Bmi1 and MLL/Hoxa9 axis in establishment of normal hematopoietic and leukemic stem cells. Cell Stem Cell, 8(6), 649–662. doi:10.1016/j.stem.2011.05.004