title: Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia.
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.
authors.affiliation: 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;
authors.forename: Grace J
authors.initials: GJ
authors.lastname: Liu
authors.affiliation: 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;
authors.forename: Luisa
authors.initials: L
authors.lastname: Cimmino
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria;
authors.forename: Julian G
authors.initials: JG
authors.lastname: Jude
authors.affiliation: Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Victoria, Australia;
authors.forename: Yifang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 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;
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Witkowski
authors.affiliation: 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;
authors.forename: Mark D
authors.initials: MD
authors.lastname: McKenzie
authors.affiliation: 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;
authors.forename: Mutlu
authors.initials: M
authors.lastname: Kartal-Kaess
authors.affiliation: 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;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Best
authors.affiliation: 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;
authors.forename: Laura
authors.initials: L
authors.lastname: Tuohey
authors.affiliation: 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;
authors.forename: Yang
authors.initials: Y
authors.lastname: Liao
authors.affiliation: 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;
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Farrar
authors.affiliation: 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;
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: 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.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria;
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: 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;
authors.forename: Ross A
authors.initials: RA
authors.lastname: Dickins
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051757:PAX5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D050799:STAT5 Transcription Factor
keywords: B-ALL; PAX5; differentiation; leukemia; transcription factor