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dc.contributor.authorWong, P
dc.contributor.authorIwasaki, M
dc.contributor.authorSomervaille, TCP
dc.contributor.authorSo, CWE
dc.contributor.authorCleary, ML
dc.date.accessioned2018-08-31T10:59:12Z
dc.date.issued2007-11-01
dc.identifier21
dc.identifier.citationGENES & DEVELOPMENT, 2007, 21 pp. 2762 - 2774
dc.identifier.issn0890-9369
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2475
dc.identifier.doi10.1101/gad.1602107
dc.description.abstractOncogenic 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.
dc.format.extent2762 - 2774
dc.languageeng
dc.language.isoeng
dc.publisherCOLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleMeis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential
dc.typeJournal Article
rioxxterms.versionofrecord10.1101/gad.1602107
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2007-11-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfGENES & DEVELOPMENT
pubs.notesaffiliation: Cleary, ML (Reprint Author), Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. Inst Canc Res, Haemato Oncol Sect, Sutton SM2 5NG, Surrey, England. keywords: leukemia stem cells; MLL; meis1; pbx; TALE homeodomain proteins keywords-plus: ACUTE LYMPHOBLASTIC-LEUKEMIA; MYELOID PROGENITORS; FREQUENT COEXPRESSION; ONCOGENIC ACTIVATION; FUSION TRANSCRIPT; HOX GENES; TRANSFORMATION; EXPRESSION; PROTEIN; PBX1 research-areas: Cell Biology; Developmental Biology; Genetics & Heredity web-of-science-categories: Cell Biology; Developmental Biology; Genetics & Heredity author-email: [email protected] orcid-numbers: Somervaille, Tim/0000-0002-9188-4379 funding-acknowledgement: NCI NIH HHS [R37 CA042971, R01 CA055029, CA55029, CA42971] number-of-cited-references: 59 times-cited: 177 usage-count-last-180-days: 0 usage-count-since-2013: 7 journal-iso: Genes Dev. doc-delivery-number: 226WB unique-id: ISI:000250618100008 oa: gold_or_bronze da: 2018-08-30
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR
pubs.volume21
pubs.embargo.termsNot known
dc.contributor.icrauthorSo, Chi Wai Ericen


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