Journal article
Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia
GJ Liu, L Cimmino, JG Jude, Y Hu, MT Witkowski, MD McKenzie, M Kartal-Kaess, SA Best, L Tuohey, Y Liao, W Shi, CG Mullighan, MA Farrar, SL Nutt, GK Smyth, J Zuber, RA Dickins
Genes and Development | Published : 2014
Abstract
Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur in most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation of undifferen-tiated lymphoblasts. Although PAX5 mutation is a critical driver of B-ALL development in mice and humans, it remains unclear how its loss contributes to leukemogenesis and whether ongoing PAX5 deficiency is required for B-ALL maintenance. Here we used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL. In this model, rest..
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Awarded by National Cancer Institute
Funding Acknowledgements
We thank M. Salzone, M. Dayton, P. Kennedy, K. Stoev, C. Smith, L. Wilkins, M. Howell, T. Carle, E. Lanera, S. Brown, and other Walter and Eliza Hall Institute Bioservices staff; W. Alexander for embryonic stem cell resources; E. Viney and J. Sarkis at the Australian Phenomics Network Transgenic RNAi service; M. Everest and M. Tinning at the Australian Genome Research Facility; and R. Lane, T. Willson, J. Corbin, and C. Hyland for technical expertise. We thank S. Lowe for vectors, D. Largaespada for Vav-tTA transgenic mice, and M. Jaritz and M. Busslinger for Pax5 ChIP-seq data. We thank S. Chappaz, D. Tarlinton, D. Hilton, M. Busslinger, and S. Lowe for advice and discussions. This work was supported by the National Health and Medical Research Council (NHMRC) of Australia project grants 575535, 1024599, and 1023454; Australian Government NHMRC Independent Research Institute Infrastructure Support Scheme (MISS); an Australian Research Council Future Fellowship (to S.L.N.); an NHMRC Research Fellowship (to G.K.S.); National Institutes of Health USA grants R01 CA151845 and CA154998 (to M.A.F.); Austrian Science Fund grant F4710-B20 (to J.Z.); Boehringer Ingelheim Institutional funding (to J.Z. and J.G.J.); the Leukaemia Foundation of Australia (G.J.L., M.T.W., and M.D.M.); a Sylvia and Charles Viertel Charitable Foundation Fellowship (to R.A.D.); Victorian State Government Operational Infrastructure Support grants; and a Victorian Endowment for Science, Knowledge, and Innovation (VESKI) Fellowship (to R.A.D.).