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

Abstract

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 p16(Ink4a)/p19(ARF) 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.

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…73 In a separate study, the same group found that such CTL responses were not limited to the immunodominant WT1 [126][127][128][129][130][131][132][133][134] epitope, but could also be directed against other HLA-A*0201-restricted WT1-derived epitopes (WT1 [37][38][39][40][41][42][43][44][45] , WT1 [187][188][189][190][191][192][193][194][195] and WT1 [235][236][237][238][239][240][241][242][243] ). 88 A similar observation was made regarding PRAME, which is known to contain at least four different HLA-A*0201-restricted epitopes that can be naturally recognized (PRA [100][101][102][103][104][105][106][107][108] , PRA 142-151 , PRA 300-309 and PRA [425][426][427][428][429]...…”

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

“…Especially, expression of Bmi1, which is required for self-renewal in HSCs and leukemic stem cells is elevated in GMPs. 32 Of importance in regard to chemotherapy resistance of AML is also the upregulated expression of Mcl1 in GMPs of Cebpa K/L x Flt3 ITD/ þ chimeras. Expression of the pro-survival gene Mcl1, a member of the BCL2 family and a crucial regulator of HSC survival, has been implicated in the pathogenesis of AML.…”

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

“…Homozygous null Pcgf4/Bmi1 mouse mutant phenotypes are attributed mainly to the depletion of the classical cPRC1 complexes (Table 4). Pcgf4/Bmi1 functions required for postnatal stem cell maintenance of multiple tissues including hematopoietic [306,307] and neural [308,309]. Pcgf4/Bmi1 null mutant mice are viable but display progressive postnatal growth retardation, defect in hematopoiesis and neurological abnormalities manifested by seizures [148].…”

“…Genome-wide studies suggested that PRC1.5 complexes encompassing CK2 and AUTS2 are recruited to active genes, uncovering a new function of the PRC1.5 in activating transcription ( [313] and see below). [148,306,307,310] CK2 belongs to the serine/threonine-selective protein kinase family. CK2 is consisted of two α (α and α') and two β (β and β') subunits, foremost of which α is responsible for the catalytic and β for the regulatory activity.…”