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Transcriptional control and signal transduction, cell cycle

PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia

Leukemia volume 30, pages 1375–1387 (2016)Cite this article

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Abstract

The Ets family transcription factor PU.1 and the interferon regulatory factor (IRF)4 and IRF8 regulate gene expression by binding to composite DNA sequences known as Ets/interferon consensus elements. Although all three factors are expressed from the onset of B-cell development, single deficiency of these factors in B-cell progenitors only mildly impacts on bone marrow B lymphopoiesis. Here we tested whether PU.1 cooperates with IRF factors in regulating early B-cell development. Lack of PU.1 and IRF4 resulted in a partial block in development the pre-B-cell stage. The combined deletion of PU.1 and IRF8 reduced recirculating B-cell numbers. Strikingly, all PU.1/IRF4 and ~50% of PU.1/IRF8 double deficient mice developed pre-B-cell acute lymphoblastic leukemia (B-ALL) associated with reduced expression of the established B-lineage tumor suppressor genes, Ikaros and Spi-B. These genes are directly regulated by PU.1/IRF4/IRF8, and restoration of Ikaros or Spi-B expression inhibited leukemic cell growth. In summary, we demonstrate that PU.1, IRF4 and IRF8 cooperate to regulate early B-cell development and to prevent pre-B-ALL formation.

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Acknowledgements

We thank M Reth and T Mak for mice, J Leahy for animal husbandry and the institute flow cytometry facility for excellent technical assistance. We thank Markus Jaritz for bioinformatic analysis. This work was supported by program and project grants (APP1054925 to SLN and 637345 to SC) and fellowships (APP1058238 to SLN) from the National Health and Medical Research Council (NHRMC) of Australia. SHMP was supported by the Leukaemia Foundation of Australia and SC by an NHMRC Career Development Fellowship. Research of the Busslinger group was supported by Boehringer Ingelheim and an ERC Advanced Grant (291740-LymphoControl). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS.

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Author notes

  1. R A Dickins

    Present address: 5Current address: Monash University, Australian Center for Blood Diseases, The Alfred, Commercial Road, Melbourne, Victoria 3004, Australia,

  2. S Carotta

    Present address: 6Current address: Boehringer Ingelheim RCV, New Therapeutic Drug Concepts, Dr Boehringer Gasse 5-11, Vienna A-1121, Austria,

Authors and Affiliations

  1. Molecular Immunology Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    S H M Pang, P Gangatirkar, Z Zheng, R A Dickins, L M Corcoran, N D Huntington, S L Nutt & S Carotta

  2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

    S H M Pang, P Gangatirkar, R A Dickins, L M Corcoran, N D Huntington, S L Nutt & S Carotta

  3. The Institute of Molecular Pathology, Vienna, Austria

    M Minnich, A Ebert & M Busslinger

  4. Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA

    G Song & C G Mullighan

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Pang, S., Minnich, M., Gangatirkar, P. et al. PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia. Leukemia 30, 1375–1387 (2016). https://doi.org/10.1038/leu.2016.27

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