IWASAKI Masayuki
   Department   Research Institutes and Facilities, Research Institutes and Facilities
   Position   Assistant Professor
Article types Original article
Language English
Peer review Peer reviewed
Title Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential.
Journal Formal name:Genes & development
Abbreviation:Genes Dev
ISSN code:08909369/08909369
Domestic / ForeginForegin
Volume, Issue, Page 21(21),pp.2762-74
Author and coauthor Wong Piu, Iwasaki Masayuki, Somervaille Tim C P, So Chi Wai Eric, So Chai Wai Eric, Cleary Michael L
Authorship 2nd author
Publication date 2007/11
Summary 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.
DOI 10.1101/gad.1602107
PMID 17942707