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Genes Dev. 2014 Jun 15;28(12):1337-50. doi: 10.1101/gad.240416.114.

Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia.

Author information

1
Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia;
2
Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria;
3
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia;
4
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia; Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria 3010, Australia;
5
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
6
Department of Laboratory Medicine and Pathology, Center for Immunology, The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA;
7
Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia; Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
8
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia; Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria 3010, Australia.

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.

KEYWORDS:

B-ALL; PAX5; differentiation; leukemia; transcription factor

PMID:
24939936
PMCID:
PMC4066403
DOI:
10.1101/gad.240416.114
[Indexed for MEDLINE]
Free PMC Article

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