title: 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.
authors.affiliation: Leukaemia and Stem Cell Biology Lab, Department of Haematological Medicine, King's College London, London SE5 9NU, UK.
authors.forename: Lan-Lan
authors.initials: LL
authors.lastname: Smith
authors.forename: Jenny
authors.initials: J
authors.lastname: Yeung
authors.forename: Bernd B
authors.initials: BB
authors.lastname: Zeisig
authors.forename: Nikolay
authors.initials: N
authors.lastname: Popov
authors.forename: Ivo
authors.initials: I
authors.lastname: Huijbers
authors.forename: Josephine
authors.initials: J
authors.lastname: Barnes
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Wilson
authors.forename: Erdogan
authors.initials: E
authors.lastname: Taskesen
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Jesús
authors.initials: J
authors.lastname: Gil
authors.forename: Maarten
authors.initials: M
authors.lastname: Van Lohuizen
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D012097:Repressor Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: C489421:Bmi1 protein, mouse; D018398:Homeodomain Proteins; C551356:MLL-AF9 fusion protein, mouse; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C097899:homeobox protein HOXA9; D063150:Polycomb Repressive Complex 1