{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T01:30:54Z","timestamp":1793669454445,"version":"4.5.1"},"reference-count":149,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Since the first clinical report in 2013, inhibitors of the intracellular kinase BTK (BTKi) have profoundly altered the treatment paradigm of B cell malignancies, replacing chemotherapy with targeted agents in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstr\u00f6m\u2019s macroglobulinemia. There are over 20 BTKi, both irreversible and reversible, in clinical development. While loss-of-function (LoF) mutations in the<jats:italic>BTK<\/jats:italic>gene cause the immunodeficiency X-linked agammaglobulinemia, neither inherited, nor somatic<jats:italic>BTK<\/jats:italic>driver mutations are known. Instead, BTKi-sensitive malignancies are addicted to BTK. BTK is activated by upstream surface receptors, especially the B cell receptor (BCR) but also by chemokine receptors, and adhesion molecules regulating B cell homing. Consequently, BTKi therapy abrogates BCR-driven proliferation and the tissue homing capacity of the malignant cells, which are being redistributed into peripheral blood. BTKi resistance can develop over time, especially in MCL and high-risk CLL patients. Frequently, resistance mutations affect the BTKi binding-site, cysteine 481, thereby reducing drug binding. Less common are gain-of-function (GoF) mutations in downstream signaling components, including phospholipase C\u03b32 (PLC\u03b32). In a subset of patients, mechanisms outside of the BCR pathway, related e.g. to resistance to apoptosis were described. BCR signaling depends on many proteins including SYK, BTK, PI3K; still based on the resistance pattern, BTKi therapy only selects GoF alterations in the NF-\u03baB arm, whereas an inhibitor of the p110\u03b4 subunit of PI3K instead selects resistance mutations in the RAS-MAP kinase pathway. BTK and PLC\u03b32 resistance mutations highlight BTK\u2019s non-redundant role in BCR-mediated NF-\u03baB activation. Of note, mutations affecting BTK tend to generate clone sizes larger than alterations in PLC\u03b32. This infers that BTK signaling may go beyond the PLC\u03b32-regulated NF-\u03baB and NFAT arms. Collectively, when comparing the primary and acquired mutation spectrum in BTKi-sensitive malignancies with the phenotype of the corresponding germline alterations, we find that certain observations do not readily fit with the existing models of BCR signaling.<\/jats:p>","DOI":"10.3389\/fimmu.2021.689472","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T08:57:03Z","timestamp":1623315423000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":68,"title":["Resistance Mutations to BTK Inhibitors Originate From the NF-\u03baB but Not From the PI3K-RAS-MAPK Arm of the B Cell Receptor Signaling Pathway"],"prefix":"10.3389","volume":"12","author":[{"given":"C. I. 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