<i>Meis1</i> is an essential and rate-limiting regulator of <i>MLL</i> leukemia stem cell potential
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ICR Authors
Authors
Wong, P
Iwasaki, M
Somervaille, TCP
So, CWE
Cleary, ML
Iwasaki, M
Somervaille, TCP
So, CWE
Cleary, ML
Document Type
Journal Article
Date
2007-11-01
Date Accepted
Abstract
<jats:p>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 <jats:italic>Hox</jats:italic> genes is likely to be critical for LSC induction and maintenance but alone it does not recapitulate the phenotype and biology of <jats:italic>MLL</jats:italic> 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 <jats:italic>MLL</jats:italic> transformation requires <jats:italic>Meis1</jats:italic> and is codependent on the redundant contributions of <jats:italic>Pbx2</jats:italic> and <jats:italic>Pbx3</jats:italic>. <jats:italic>Meis1</jats:italic> 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 <jats:italic>MLL</jats:italic> leukemogenesis.</jats:p>
Citation
GENES & DEVELOPMENT, 2007, 21 pp. 2762 - 2774
Source Title
Publisher
Cold Spring Harbor Laboratory
ISSN
0890-9369