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Multiple myeloma gammopathies

The transcription factor IRF4 represses proapoptotic BMF and BIM to licence multiple myeloma survival

Leukemia volume 35, pages 2114–2118 (2021)Cite this article

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Multiple myeloma (MM) is an incurable cancer of antibody secreting plasma cells. Globally, it accounts for ~15% of all hematological malignancies and is second only to non-Hodgkin’s lymphoma. While outcomes for patients with MM have improved with the introduction of the immunomodulatory drugs and proteasome inhibitors (PIs), patients invariably relapse, with the 5-year survival rate currently standing at 52.7% [1].

MM is a complex malignancy that is characterized by significant disease heterogeneity. Despite this heterogeneity, a seminal study by Shaffer et al. using RNA interference established that knockdown of the transcription factor interferon regulatory factor 4 (IRF4), which is rarely mutated in MM, was toxic to all MM cell lines examined [2]. Using microarray experiments, IRF4 was reported to maintain the expression of genes associated with many essential cellular processes including metabolism, cell cycle progression, cell death, transcriptional regulation, and plasmacytic differentiation, which led to the conclusion that IRF4 loss results in “death by a thousand cuts”. However, with the exception of the transcription factor MYC and its impact on proliferation, IRF4 targets directly responsible for the loss in MM viability were never identified. Furthermore, although prior studies established that IRF4 could function as both an activator and repressor of transcription [3,4,5], there is little insight on the role of IRF4 with respect to the latter.

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Fig. 1: IRF4 loss results in cell cycle inhibition and death of MM cells.
Fig. 2: IRF4 maintains MM survival through the repression of BMF alone or in combination with BCL2L11.

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Acknowledgements

We acknowledge the help of the Walter and Eliza Hall Institute and Flow Cytometry Core Facilities. We also thank Daniel H.D. Gray for helpful discussions. This work was supported by grants from the National Health and Medical Research Council (Project grants 1143105 (MJH), 1128609 (WS); Ideas grant 1184523 (SLN and SNW); Program grant 1113133 (DCSH)), the Leukemia & Lymphoma Society-Snowdome Foundation-Leukaemia Foundation (LLS-SF-LF; 6592-20) Translational Research Program (TRP) (SLN and SNW), the Leukemia and Lymphoma Society SCOR grant 7015–18 (DCSH and MJH), and the Cancer Council Victoria Grant-in-Aid Project grants 1102662 (SLN) and 1161400 (LAO’R). This work was also supported by fellowships awarded to SLN (NHMRC; 1155342), DCSH (NHMRC; 1156024), MJH (NHMRC; 1156095), SNW (Walter and Eliza Hall Trust Centenary Fellowship), PLF (Cancer Council of Victoria Postdoctoral Research Fellowship), MSYL (NHMRC/RACP CRB Blackburn scholarship; 1075151), WS (Walter and Eliza Hall Institute Centenary Fellowship sponsored by Commonwealth Serum Laboratories Limited), and YY (China Scholarship Council).

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  1. These authors contributed equally: Stephen L. Nutt, Simon N. Willis

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia

    Pasquale L. Fedele, Yang Liao, Jia-nan Gong, Yuan Yao, Mark F. van Delft, Lin Tai, Marco J. Herold, Jacob T. Jackson, Charis E. Teh, Tania Tan, Lorraine A. O’Reilly, Julie Tellier, David C. S. Huang, Wei Shi, Stephen L. Nutt & Simon N. Willis

  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3010, Australia

    Pasquale L. Fedele, Yang Liao, Jia-nan Gong, Yuan Yao, Mark F. van Delft, Marco J. Herold, Jacob T. Jackson, Charis E. Teh, Lorraine A. O’Reilly, Julie Tellier, David C. S. Huang, Stephen L. Nutt & Simon N. Willis

  3. Haematology Department, Monash Health, Clayton, VIC, 3168, Australia

    Pasquale L. Fedele, Michael S. Y. Low & George Grigoriadis

  4. School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia

    Pasquale L. Fedele, Michael S. Y. Low & George Grigoriadis

  5. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia

    Yang Liao & Wei Shi

  6. School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia

    Yang Liao & Wei Shi

  7. School of Medicine, Tsinghua University, Beijing, China

    Yuan Yao

  8. School of Computing and Information Systems, The University of Melbourne, Parkville, VIC, 3010, Australia

    Wei Shi

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  1. Pasquale L. Fedele
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Correspondence to Stephen L. Nutt or Simon N. Willis.

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Fedele, P.L., Liao, Y., Gong, Jn. et al. The transcription factor IRF4 represses proapoptotic BMF and BIM to licence multiple myeloma survival. Leukemia 35, 2114–2118 (2021). https://doi.org/10.1038/s41375-020-01078-0

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