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Blood, 12 February 2009, Vol. 113, No. 7, pp. 1432-1443. Prepublished online as a Blood First Edition Paper on October 14, 2008; DOI 10.1182/blood-2008-06-162263. This Article Full Text Full Text (PDF) Supplemental Methods, Table, and Figures All Versions of this Article: blood-2008-06-162263v1 113/7/1432    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Heuser, M. Articles by Aparicio, S. A. Search for Related Content PubMed PubMed Citation Articles by Heuser, M. Articles by Aparicio, S. A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Loss of Mll5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation Michael Heuser1,*, Damian B. Yap2,3,*, Malina Leung1, Teresa Ruiz de Algara2, Alaeddin Tafech2, Steven McKinney2, John Dixon4, Rosemary Thresher4, Bill Colledge5, Mark Carlton4, R. Keith Humphries1,6, and Samuel A. Aparicio2,3 1 Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC; 2 Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC; 3 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC; 4 Takeda Pharmaceuticals Cambridge Ltd., Cambridge, United Kingdom; 5 Physiological Laboratory, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom; and 6 Department of Medicine, University of British Columbia, Vancouver, BC MLL5 is a divergent member of the Drosophila Trithorax-related (SET) domain and plant homeodomain (PHD) domain-containing chromatin regulators that are involved in the regulation of transcriptional "memory" during differentiation. Human MLL5 is located on chromosome 7q22, which frequently is deleted in myeloid leukemias, suggesting a possible role in hemopoiesis. To address this question, we generated a loss-of-function allele (Mll5tm1Apa) in the murine Mll5 locus. Unlike other Mll genes, Mll5tm1Apa homozygous mice are viable but display defects in immunity and hematopoiesis. First, Mll5tm1Apa homozygous mice show increased susceptibility to spontaneous eye infections, associated with a cell-autonomous impairment of neutrophil function. Second, Mll5tm1Apa/tm1Apa mice exhibit a mild impairment of erythropoiesis. Third, Mll5tm1Apa/tm1Apa hematopoietic stem cells (HSCs) have impaired competitive repopulating capacity both under normal conditions and when subjected to self-renewal stimulation by NUP98-HOXA10. Fourth, Mll5tm1Apa homozygous HSCs show a dramatic sensitivity to DNA demethylation–induced differentiation (5-azadeoxycytidine). Taken together, our data show that MLL5 is involved in terminal myeloid differentiation and the regulation of HSC self-renewal by a mechanism that involves DNA methylation. These data warrant investigation of MLL5 expression levels as a predictive marker of demethylating-agent response in patients with myelodysplastic syndromes and leukemias and identify MLL5 as a key regulator of normal hematopoiesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: MLL5 governs hematopoiesis: a step closer Han Liu, Todd D. Westergard, and James J.-D. Hsieh Blood 2009 113: 1395-1396. [Full Text] [PDF] This article has been cited by other articles: M. I. Mascarenhas, A. Parker, E. Dzierzak, and K. Ottersbach Identification of novel regulators of hematopoietic stem cell development through refinement of stem cell localization and expression profiling Blood, November 19, 2009; 114(21): 4645 - 4653. [Abstract] [Full Text] [PDF] M. Heuser, L. M. Sly, B. Argiropoulos, F. Kuchenbauer, C. Lai, A. Weng, M. Leung, G. Lin, C. Brookes, S. Fung, et al. Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal Blood, November 5, 2009; 114(19): 3983 - 3993. [Abstract] [Full Text] [PDF] S. Sebastian, P. Sreenivas, R. Sambasivan, S. Cheedipudi, P. Kandalla, G. K. Pavlath, and J. Dhawan MLL5, a trithorax homolog, indirectly regulates H3K4 methylation, represses cyclin A2 expression, and promotes myogenic differentiation PNAS, March 24, 2009; 106(12): 4719 - 4724. [Abstract] [Full Text] [PDF] H. Liu, T. D. Westergard, and J. J.-D. Hsieh MLL5 governs hematopoiesis: a step closer Blood, February 12, 2009; 113(7): 1395 - 1396. [Full Text] [PDF]

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