Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia
- Liu, GJ; Cimmino, L; Jude, JG; Hu, Y; Witkowski, MT; McKenzie, MD; Kartal-Kaess, M; Best, SA; Tuohey, L; Liao, Y; Shi, W; Mullighan, CG; Farrar, MA; Nutt, SL; Smyth, GK; Zuber, J; Dickins, RA;
Publication Year 2014-06-15, Volume 28, Issue #12, Page 1337-50
- Journal Title
- Genes Dev
- Publication Type
- Journal Article
- 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 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.
- CSH Press
- PAX5 ; leukemia ; B-ALL ; differentiation ; transcription factor
- WEHI Research Division(s)
- Molecular Medicine; Molecular Immunology; Bioinformatics
- Publisher's Version
- Rights Notice
- 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.ezp.lib.unimelb.edu.au/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/.
Creation Date: 2014-06-20 07:46:27Last Modified: 2015-05-26 09:41:48