Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia (original) (raw)

1. Luisa Cimmino1,2,10,
2. Julian G. Jude3,
3. Yifang Hu4,
4. Matthew T. Witkowski1,2,
5. Mark D. McKenzie1,2,
6. Mutlu Kartal-Kaess1,2,
7. Sarah A. Best1,2,
8. Laura Tuohey1,2,
9. Yang Liao4,5,
10. Wei Shi4,5,
11. Charles G. Mullighan6,
12. Michael A. Farrar7,
13. Stephen L. Nutt2,8,
14. Gordon K. Smyth4,9,
15. Johannes Zuber3 and
16. Ross A. Dickins1,2,11
17. 1Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
18. 2Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia;
19. 3Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria;
20. 4Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia;
21. 5Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria 3010, Australia;
22. 6Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA;
23. 7Department of Laboratory Medicine and Pathology, Center for Immunology, The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA;
24. 8Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
25. 9Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria 3010, Australia

• ↵10 Present address: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.

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.

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

Footnotes

• ↵11 Corresponding author
  E-mail rdickins{at}wehi.edu.au

• Supplemental material is available for this article.

• Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.240416.114.

• Received February 23, 2014.

• Accepted May 15, 2014.

• © 2014 Liu et al.; Published by Cold Spring Harbor Laboratory Press

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