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Stem Cells

Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis

Leukemia volume 24, pages 1732–1741 (2010)Cite this article

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Abstract

The mixed lineage leukemia (MLL) gene is disrupted by chromosomal translocations in acute leukemia, producing a fusion oncogene with altered properties relative to the wild-type gene. Murine loss-of-function studies have shown an essential role for Mll in developing the haematopoietic system, yet studies using different conditional knockout models have yielded conflicting results regarding the requirement for Mll during adult steady-state haematopoiesis. In this study, we used a loxP-flanked Mll allele (MllF) and a developmentally regulated, haematopoietic-specific VavCre transgene to reassess the consequences of Mll loss in the haematopoietic lineage, without the need for inducers of Cre recombinase. We show that VavCre;Mll mutants exhibit phenotypically normal fetal haematopoiesis, but rarely survive past 3 weeks of age. Surviving animals are anemic, thrombocytopenic and exhibit a significant reduction in bone marrow haematopoietic stem/progenitor populations, consistent with our previous findings using the inducible Mx1Cre transgene. Furthermore, the analysis of VavCre mutants revealed additional defects in B-lymphopoiesis that could not be assessed using Mx1Cre-mediated Mll deletion. Collectively, these data support the conclusion that Mll has an essential role in sustaining postnatal haematopoiesis.

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Acknowledgements

We thank our laboratory members, David Traver and Christopher Dant for insightful comments and suggestions, Dr Roderick Bronson, Dr Benjamin Lee and Dr Glen Raffel for histolology advice, and Dr Hanna Mikkola, Dr Matthias Stadtfeld and Dr Thomas Graf for VavCre mice and advice for breeding and analyzing this strain. We are grateful to Nancy Speck for advice and use of her microscopes. This work was supported by the NIH grant HL090036 to PE and NCRR COBRE grant P20RR016437 to William Green.

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  1. T Gan and C D Jude: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH, USA

    T Gan, C D Jude, K Zaffuto & P Ernst

  2. Department of Microbiology and Immunology, Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH, USA

    P Ernst

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  1. T Gan
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Correspondence to P Ernst.

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Gan, T., Jude, C., Zaffuto, K. et al. Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis. Leukemia 24, 1732–1741 (2010). https://doi.org/10.1038/leu.2010.171

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