{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:09:37Z","timestamp":1788286177976,"version":"build-2803163510"},"reference-count":118,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ruth L. Kirschstein National Research Service Award for Individual Predoctoral Fellows","award":["1F31CA275378"],"award-info":[{"award-number":["1F31CA275378"]}]},{"name":"the Ruth L. Kirschstein National Research Service Award for Individual Predoctoral Fellows","award":["R35GM151109"],"award-info":[{"award-number":["R35GM151109"]}]},{"name":"the Ruth L. Kirschstein National Research Service Award for Individual Predoctoral Fellows","award":["K08CA230319"],"award-info":[{"award-number":["K08CA230319"]}]},{"name":"the NIGMS\/NIH","award":["1F31CA275378"],"award-info":[{"award-number":["1F31CA275378"]}]},{"name":"the NIGMS\/NIH","award":["R35GM151109"],"award-info":[{"award-number":["R35GM151109"]}]},{"name":"the NIGMS\/NIH","award":["K08CA230319"],"award-info":[{"award-number":["K08CA230319"]}]},{"name":"NCI\/NIH","award":["1F31CA275378"],"award-info":[{"award-number":["1F31CA275378"]}]},{"name":"NCI\/NIH","award":["R35GM151109"],"award-info":[{"award-number":["R35GM151109"]}]},{"name":"NCI\/NIH","award":["K08CA230319"],"award-info":[{"award-number":["K08CA230319"]}]},{"name":"the Doris Duke Charitable Foundation","award":["1F31CA275378"],"award-info":[{"award-number":["1F31CA275378"]}]},{"name":"the Doris Duke Charitable Foundation","award":["R35GM151109"],"award-info":[{"award-number":["R35GM151109"]}]},{"name":"the Doris Duke Charitable Foundation","award":["K08CA230319"],"award-info":[{"award-number":["K08CA230319"]}]},{"name":"the Edward P. Evans Foundation","award":["1F31CA275378"],"award-info":[{"award-number":["1F31CA275378"]}]},{"name":"the Edward P. Evans Foundation","award":["R35GM151109"],"award-info":[{"award-number":["R35GM151109"]}]},{"name":"the Edward P. Evans Foundation","award":["K08CA230319"],"award-info":[{"award-number":["K08CA230319"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Bruton\u2019s tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) signaling pathway and confers anti-apoptotic and proliferative properties to malignant B-cells in chronic lymphocytic leukemia (CLL). Small molecule BTK inhibitors were designed to bind BTK\u2019s active site and block downstream signaling. These drugs have now been used in the treatment of thousands of patients with CLL, the most common form of leukemia in the western hemisphere. However, adverse effects of early generations of BTK inhibitors and resistance to treatment have led to the development of newer, more selective and non-covalent BTK inhibitors. As the use of these newer generation BTK inhibitors has increased, novel BTK resistance mutations have come to light. This review aims to discuss previously known and novel BTK mutations, their mechanisms of resistance, and their relationship with patient treatment. Also discussed here are future studies that are needed to investigate the underlying cause allowing these mutations to occur and how they incite resistance. New treatments on the horizon that attempt to maneuver around these resistance mutations can be met with new resistance mutations, creating an unmet need for patients with CLL. Novel therapies and combinations that address all forms of resistance are discussed.<\/jats:p>","DOI":"10.3390\/genes14122182","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T03:48:41Z","timestamp":1701834521000},"page":"2182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL)"],"prefix":"10.3390","volume":"14","author":[{"given":"Alexandra","family":"Chirino","sequence":"first","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2094-6923","authenticated-orcid":false,"given":"Skye","family":"Montoya","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Safronenka","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4407-6325","authenticated-orcid":false,"given":"Justin","family":"Taylor","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1182\/blood.V96.1.9","article-title":"Fates of human B-cell precursors","volume":"96","author":"LeBien","year":"2000","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1056\/NEJM199510193331606","article-title":"Chronic lymphocytic leukemia","volume":"333","author":"Rozman","year":"1995","journal-title":"N. 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