Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation.
The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. Meis1 and Pbx1 interaction domain-swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when cotransduced in primary cells engineered to overexpress Hoxa9, thus implying a modular nature for PIM in Meis1-accelerated transformation. Moreover, we show that the transactivating domain of VP16 can restore, and even enhance, the oncogenic potential of the Meis1 mutant lacking the C-terminal 49 amino acids. In contrast to Meis1, the fusion VP16-Meis1 is spontaneously oncogenic, and all leukemias harbor genetic activation of endogenous Hoxa9 and/or Hoxa7, suggesting that Hoxa gene activation represents a key event required for the oncogenic activity of VP16-Meis1.
Laboratory of Molecular Genetics of Stem Cells, Institute of Research in Immunology and Cancer (IRIC), Université de Montréal, QC, Canada.
Aline
A
Mamo
Jana
J
Krosl
Evert
E
Kroon
Janet
J
Bijl
Alexander
A
Thompson
Nadine
N
Mayotte
Simon
S
Girard
Richard
R
Bisaillon
Nathalie
N
Beslu
Mark
M
Featherstone
Guy
G
Sauvageau
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D017405:Herpes Simplex Virus Protein Vmw65 / Q000502:physiology; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D007938:Leukemia / Q000209:etiology* / Q000473:pathology; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation / Q000502:physiology*; D014161:Transduction, Genetic
D017405:Herpes Simplex Virus Protein Vmw65; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein; D011495:Histone-Lysine N-Methyltransferase