Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia
Details
Publication Year 2014-06-15, Volume 28, Issue #12, Page 1337-50
Journal Title
Genes Dev
Publication Type
Journal Article
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 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.
Publisher
CSH Press
Keywords
PAX5 ; leukemia ; B-ALL ; differentiation ; transcription factor
WEHI Research Division(s)
Molecular Medicine; Molecular Immunology; Bioinformatics
NHMRC Grants
NHMRC/575535 NHMRC/1024599 NHMRC/1023454
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 07:46:27
Last Modified: 2015-05-26 09:41:48
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