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

Grace 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, Ross A. Dickins

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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 undifferen-tiated 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.

Original languageEnglish (US)
Pages (from-to)1337-1350
Number of pages14
JournalGenes and Development
Volume28
Issue number12
DOIs
StatePublished - Jun 15 2014

Keywords

  • B-ALL
  • Differentiation
  • Leukemia
  • PAX5
  • Transcription factor

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