Genomic evolution of ibrutinib‐resistant clones in Waldenström macroglobulinaemia
- 27 February 2020
- journal article
- research article
- Published by Wiley in British Journal of Haematology
- Vol. 189 (6), 1165-1170
- https://doi.org/10.1111/bjh.16463
Abstract
Ibrutinib is highly active in Waldenström macroglobulinaemia (WM) patients, but disease progression can occur due to acquired mutations in BTK, the target of ibrutinib, or PLCG2, the protein downstream of BTK. However, not all resistant patients harbour these alterations. We have performed a whole‐exome sequencing study to identify alternative molecular mechanisms that can drive ibrutinib resistance. Our findings include deletions on chromosomes 6q, including homozygous deletions, and 8p, which encompass key regulators of BTK, MYD88/NF‐κB, and apoptotic signalling. Moreover, we have identified recurring mutations in ubiquitin ligases, innate immune signalling, and TLR/MYD88 pathway regulators in ibrutinib‐resistant WM patients.Keywords
Funding Information
- International Waldenstrom's Macroglobulinemia Foundation
- Leukemia and Lymphoma Society
- American Society of Hematology (ASH Scholar Award)
- National Cancer Institute (Development Award: Spore 5P50CA100707‐12)
- Fundación Española de Hematología y Hemoterapia
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