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Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities

  • Focussed Research Review
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Oncogenic MYD88 mutations, most notably the Leu 265 Pro (L265P) mutation, were recently identified as potential driver mutations in various B-cell non-Hodgkin Lymphomas (NHLs). The L265P mutation is now thought to be common to virtually all NHLs and occurs in between 4 and 90% of cases, depending on the entity. Since it is tumor-specific, the mutation, and the pathways it regulates, might serve as advantageous therapeutic targets for both conventional chemotherapeutic intervention, as well as immunotherapeutic strategies. Here, we review recent progress on elucidating the molecular and cellular processes affected by the L265P mutation of MYD88, describe a new in vivo model for MyD88 L265P-mediated oncogenesis, and summarize how these findings could be exploited therapeutically by specific targeting of signaling pathways. In addition, we summarize current and explore future possibilities for conceivable immunotherapeutic approaches, such as L265P-derived peptide vaccination, adoptive transfer of L265P-restricted T cells, and use of T-cell receptor-engineered T cells. With clinical trials regarding their efficacy rapidly expanding to NHLs, we also discuss potential combinations of immune checkpoint inhibitors with the described targeted chemotherapies of L265P signaling networks, and/or with the above immunological approaches as potential ways of targeting MYD88-mutated lymphomas in the future.

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Abbreviations

BTK:

Bruton’s tyrosine kinase

CIB:

Checkpoint inhibitor blockade

CLL:

Chronic lymphocytic leukemia

DD:

Death domain

DLBCL:

Diffuse large B-cell lymphoma

GMP:

Good manufacturing practice

HEK:

Human embryonic kidney

HL:

Hodgkin lymphoma

HLA:

Human leukocyte antigen

IFN:

Interferon

IL:

Interleukin

IL-1R:

IL-1 receptor

iODN:

Inhibitory oligodeoxynucleotides

IRAK:

IL-1R-associated kinase

JAK:

Janus kinase

L265P:

Leu 265 Pro

MGUS:

Monoclonal gammopathy of undetermined significance

MHC:

Major histocompatibility complex

MyD88:

Myeloid differentiation 88

NF-κB:

Nuclear factor κ B

NHL:

Non-Hodgkin lymphoma

PCNSL:

Primary central nervous system lymphoma

PMBCL:

Primary mediastinal large B-cell lymphoma

PTIT:

Peptide-based T-cell-mediated immunotherapy

TAK1:

Transforming growth factor beta-activated kinase 1

TCR:

T-cell receptor

TIR:

Toll/Interleukin-1 (IL-1) receptor

TLR:

Toll-like receptor

WM:

Waldenström’s macroglobulinemia

WT:

Wild type

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Acknowledgements

We thank Hans-Georg Rammensee, Stefan Stevanović, Juliane Walz and Annika Nelde for helpful discussions. Free clipart was from pngtree (human-body-structure_3520512, cartoon-syringe_1100816) or thenounproject (skull-and-crossbones/9626).

Funding

This work was supported by Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Center (SFB) 685 “Immunotherapy” (to Y. Cardona Gloria, A. Weber and O.-O. Wolz), the Federal State Baden-Württemberg Junior Professor Program (to A. Weber), the University of Tübingen and the Medical Faculty Tübingen (Fortüne Junior Grant to O.-O. Wolz) as well as by DAAD support (Özcan Çınar).

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Authors and Affiliations

  1. Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany

    Alexander N. R. Weber, Yamel Cardona Gloria, Özcan Çınar & Olaf-Oliver Wolz

  2. Berlin Institute for Health Charité and Max-Delbrück Center, Campus Buch, Building 42-53, Lindenberger Weg 80, 13125, Berlin, Germany

    Antonio Pezzutto

  3. Department of Hematology, Oncology and Tumor Immunology, Charité Medical School, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany

    Antonio Pezzutto

  4. Clinic I of Internal Medicine, University Hospital of Cologne, Cologne, Germany

    H. Christian Reinhardt

  5. Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    H. Christian Reinhardt

  6. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

    H. Christian Reinhardt

Authors
  1. Alexander N. R. Weber
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  2. Yamel Cardona Gloria
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  3. Özcan Çınar
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  4. H. Christian Reinhardt
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  5. Antonio Pezzutto
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  6. Olaf-Oliver Wolz
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Contributions

All authors collected and analyzed data, A. Weber coordinated the study and drafted the manuscript, and all authors contributed toward and approved the final manuscript.

Corresponding authors

Correspondence to Alexander N. R. Weber or Olaf-Oliver Wolz.

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Conflict of interest

OOW and AW are named inventors on a patent for the immunotherapeutic exploitation of L265P mutations. The authors declare that there are no other potential conflicts of interest.

Additional information

This Focussed Research Review is based on a presentation given at the 3rd Symposium on “Advances in Cancer Immunology and Immunotherapy”, held in Athens, Greece, November 2nd–4th, 2017. It is part of a Cancer Immunology, Immunotherapy series of papers from this conference.

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Weber, A.N.R., Cardona Gloria, Y., Çınar, Ö. et al. Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities. Cancer Immunol Immunother 67, 1797–1807 (2018). https://doi.org/10.1007/s00262-018-2242-9

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