Authors:
Lan-Lan Smith, Jenny Yeung, Bernd B. Zeisig, Nikolay Popov, Ivo Huijbers, Josephine Barnes, Amanda J. Wilson, Erdogan Taskesen, Ruud Delwel, Jesús Gil, Maarten Van Lohuizen, & Chi Wai Eric So
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.
Source:
Cell Stem Cell; Vol. 8, Issue 6, 649-662 (06/03/11)