Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential.
Oncogenic mutations of the MLL histone methyltransferase confer an unusual ability to transform non-self-renewing myeloid progenitors into leukemia stem cells (LSCs) by mechanisms that remain poorly defined. Misregulation of Hox genes is likely to be critical for LSC induction and maintenance but alone it does not recapitulate the phenotype and biology of MLL leukemias, which are clinically heterogeneous--presumably reflecting differences in LSC biology and/or frequency. TALE (three-amino-acid loop extension) class homeodomain proteins of the Pbx and Meis families are also misexpressed in this context, and we thus employed knockout, knockdown, and dominant-negative genetic techniques to investigate the requirements and contributions of these factors in MLL oncoprotein-induced acute myeloid leukemia. Our studies show that induction and maintenance of MLL transformation requires Meis1 and is codependent on the redundant contributions of Pbx2 and Pbx3. Meis1 in particular serves a major role in establishing LSC potential, and determines LSC frequency by quantitatively regulating the extent of self-renewal, differentiation arrest, and cycling, as well as the rate of in vivo LSC generation from myeloid progenitors. Thus, TALE proteins are critical downstream effectors within an essential homeoprotein network that serves a rate-limiting regulatory role in MLL leukemogenesis.
Wong
Piu
P
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Iwasaki
Masayuki
M
Somervaille
Tim C P
TC
So
Chi Wai Eric
CW
So
Chai Wai Eric
CW
Cleary
Michael L
ML
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D018816:Genes, cdc / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation / Q000401:mortality; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C490382:Pbx2 protein, mouse; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C490797:Tgif1 protein, mouse; C090466:proto-oncogene protein Pbx3; D051788:Myeloid-Lymphoid Leukemia Protein