Liu, G.Cimmino, L.Jude, J.Hu, Y.Witkowski, M.McKenzie, M.Kartal-Kaess, M.Best, S.Tuohey, L.Liao, Y.Shi, W.Mullighan, C.Farrar, M.Nutt, S.Smyth, G.Zuber, J.Dickins, R.2017-03-082017-03-082014Genes & Development, 2014; 28(12):1337-13500890-93691549-5477http://hdl.handle.net/2440/103713Loss-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 undifferentiated 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, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation. Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity. These and similar findings in human B-ALL cell lines establish that Pax5 hypomorphism promotes B-ALL self-renewal by impairing a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions. Our results establish a causal relationship between the hallmark genetic and phenotypic features of B-ALL and suggest that engaging the latent differentiation potential of B-ALL cells may provide new therapeutic entry points.en© 2014 Liu et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http:// creativecommons.org/licenses/by-nc/4.0/.PAX5; leukemia; B-ALL; differentiation; transcription factorJournal article003006120810.1101/gad.240416.1140003379910000072-s2.0-84902504214277145Mullighan, C. [0000-0002-1871-1850]