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Genomic evolution of ibrutinib‐resistant clones in Waldenström macroglobulinaemia
Author(s) -
Jiménez Cristina,
Chan Gloria G.,
Xu Lian,
Tsakmaklis Nickolas,
Kofides Amanda,
Demos Maria G.,
Chen Jiaji,
Liu Xia,
Munshi Manit,
Yang Guang,
Castillo Jorge J.,
Wiestner Adrian,
GarcíaSanz Ramón,
Treon Steven P.,
Hunter Zachary R.
Publication year - 2020
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.16463
Subject(s) - ibrutinib , bruton's tyrosine kinase , cancer research , waldenstrom macroglobulinemia , exome , biology , immunology , exome sequencing , mutation , computational biology , genetics , chronic lymphocytic leukemia , leukemia , gene , signal transduction , lymphoma , tyrosine kinase
Summary 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.