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

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dc.contributor.authorLiu, G.
dc.contributor.authorCimmino, L.
dc.contributor.authorJude, J.
dc.contributor.authorHu, Y.
dc.contributor.authorWitkowski, M.
dc.contributor.authorMcKenzie, M.
dc.contributor.authorKartal-Kaess, M.
dc.contributor.authorBest, S.
dc.contributor.authorTuohey, L.
dc.contributor.authorLiao, Y.
dc.contributor.authorShi, W.
dc.contributor.authorMullighan, C.
dc.contributor.authorFarrar, M.
dc.contributor.authorNutt, S.
dc.contributor.authorSmyth, G.
dc.contributor.authorZuber, J.
dc.contributor.authorDickins, R.
dc.date.issued2014
dc.description.abstractLoss-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.
dc.description.statementofresponsibilityGrace J. Liu, Luisa Cimmino, Julian G. Jude, Yifang Hu, Matthew T. Witkowski, Mark D. McKenzie, Mutlu Kartal-Kaess, Sarah A. Best, Laura Tuohey, Yang Liao, Wei Shi, Charles G. Mullighan, Michael A. Farrar, Stephen L. Nutt, Gordon K. Smyth, Johannes Zuber, and Ross A. Dickins
dc.identifier.citationGenes & Development, 2014; 28(12):1337-1350
dc.identifier.doi10.1101/gad.240416.114
dc.identifier.issn0890-9369
dc.identifier.issn1549-5477
dc.identifier.orcidMullighan, C. [0000-0002-1871-1850]
dc.identifier.urihttp://hdl.handle.net/2440/103713
dc.language.isoen
dc.publisherCold Spring Harbor Laboratory Press
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/575535
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1024599
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1023454
dc.relation.grantARC
dc.relation.grantNHMRC
dc.rights© 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/.
dc.source.urihttps://doi.org/10.1101/gad.240416.114
dc.subjectPAX5; leukemia; B-ALL; differentiation; transcription factor
dc.titlePax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia
dc.typeJournal article
pubs.publication-statusPublished

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