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Multiple myeloma gammopathies

Role of AID in the temporal pattern of acquisition of driver mutations in multiple myeloma

Leukemia volume 34, pages 1476–1480 (2020)Cite this article

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During the last 10 years next generation sequencing has extensively expanded our knowledge of multiple myeloma (MM) biology and pathogenesis [1, 2]. Using large whole exome and targeted sequencing datasets, several studies have comprehensively characterized the single nucleotide variants (SNVs) landscape revealing 81 potential driver genes involving different critical pathways such as MAPK and NF-κB [3,4,5]. Mutations in driver genes show a heterogeneous and often subclonal cancer cell fraction (CCF), reflecting a late role in MM development. This hypothesis was further supported by the lower prevalence of driver SNVs in MM precursor disease (i.e., monoclonal gammopathy of undetermined significance and smoldering MM) [1, 2]. Nevertheless, the order of acquisition of driver mutations in MM has never been investigated within a formal statistical framework.

The role of activation-induced cytidine deaminase (AID) and the germinal center (GC) in MM initiation has long been recognized [2]. Recent studies have suggested a potential role for repeated antigen exposure with GC reentry and AID-induced mutagenesis during the premalignant phase of MM [6,7,8]. During this early phase, the precursor cells acquire key aberrations that define distinct evolutionary trajectories towards MM [2].

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Fig. 1: Order of acquisition of mutations in driver gene in multiple myeloma.
Fig. 2: Mutational processes involved in the acquisition of mutations in driver genes.

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Acknowledgements

This work is supported by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748). BDG, DH and ML were supported by a Stand Up To Cancer—National Science Foundation—Lustgarten Foundation Convergence Dream Team Grant. BDG and DH were supported by The Pershing Square Sohn Prize-Mark Foundation Fellowship supported by funding from The Mark Foundation for Cancer Research. KHM was supported by the Haematology Society of Australia and New Zealand New Investigator Clinical Fellowship and the Royal College of Pathologists of Australasia Mike and Carole Ralston Travelling Fellowship

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  1. These authors contributed equally: Francesco Maura, Even H. Rustad

Authors and Affiliations

  1. Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Francesco Maura, Even H. Rustad, Venkata Yellapantula, Kylee H. Maclachlan, Benjamin T. Diamond, Alexander Lesokhin & Ola Landgren

  2. Department of Oncological Sciences, Tisch Cancer Institute, Center for Computational Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Marta Łuksza, David Hoyos & Benjamin D. Greenbaum

  3. Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Marta Łuksza & Benjamin D. Greenbaum

  4. Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    David Hoyos & Benjamin D. Greenbaum

  5. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Benjamin D. Greenbaum

  6. NYU Perlmutter Cancer Center, NYC, NY, 10016, USA

    Gareth Morgan

  7. Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Elli Papaemmanuil

  8. Department of Medicine, Center for Hematological Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Elli Papaemmanuil

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  1. Francesco Maura
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Contributions

FM designed the study, collected, analyzed data and wrote the paper; OL, EHR, KHM, BTD and VY analyzed data and wrote the paper; GM, AL, EP, ML and BDG analyzed data

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Correspondence to Francesco Maura.

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Maura, F., Rustad, E.H., Yellapantula, V. et al. Role of AID in the temporal pattern of acquisition of driver mutations in multiple myeloma. Leukemia 34, 1476–1480 (2020). https://doi.org/10.1038/s41375-019-0689-0

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