Multiple myeloma gammopathies

Genome instability in multiple myeloma

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by clonal proliferation of plasma cells and a heterogenous genomic landscape. Copy number and structural changes due to chromosomal instability (CIN) are common features of MM. In this review, we describe how primary and secondary genetic events caused by CIN can contribute to increased instability across the genome of malignant plasma cells; with a focus on specific driver genomic events, and how they interfere with cell-cycle checkpoints, to prompt accelerated proliferation. We also provide insight into other forms of CIN, such as chromothripsis and chromoplexy. We evaluate how the tumor microenvironment can contribute to a further increase in chromosomal instability in myeloma cells. Lastly, we highlight the role of certain mutational signatures in leading to high mutation rate and genome instability in certain MM patients. We suggest that assessing CIN in MM and its precursors states may help improve predicting the risk of progression to symptomatic disease and relapse and identifying future therapeutic targets.

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Fig. 1: Recurrent genetic alterations in multiple myeloma.
Fig. 2: Summary of chromosomal rearrangements in B-cells and aberrant translocation events in multiple myeloma.
Fig. 3: Mechanisms of chromothripsis and chromoplexy in cancer cells.
Fig. 4: Tumor-microenvironment contribution to genome instability of malignant cells.

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Acknowledgements

This review was supported in part by National Institutes of Health grant (NIH R01 CA 205954), German Society for Internal Medicine (DGIM), German Academic Scholarship Foundation, the Multiple Myeloma research Foundation (MMRF), and Leukemia and Lymphoma Society (LLS).

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Correspondence to Mark Bustoros or Irene M. Ghobrial.

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There was no commercial funding for this review. MB has advisory role and received Honoraria from Takeda and has received honoraria Dava Oncology. IMG has a consulting and advisory role with Celgene, Takeda, Bristol-Myers Squibb, Genentech, Janssen Pharmaceuticals, and Amgen, and has received research funding/honoraria from Celgene, Takeda, Bristol-Myers Squibb, Janssen Pharmaceuticals, and Amgen. The rest of the authors have no conflicts to disclose.

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Neuse, C.J., Lomas, O.C., Schliemann, C. et al. Genome instability in multiple myeloma. Leukemia (2020). https://doi.org/10.1038/s41375-020-0921-y

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