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

Author(s): 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;
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
Research Division(s): Molecular Medicine; Molecular Immunology; Bioinformatics
Publisher's Version: https://doi.org/10.1101/gad.240416.114
NHMRC Grants: NHMRC/575535, NHMRC/1024599, NHMRC/1023454,
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Creation Date: 2014-06-20 07:46:27

Last Modified: 2015-05-26 09:41:48