{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T06:29:36Z","timestamp":1784442576328,"version":"3.55.0"},"reference-count":33,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T00:00:00Z","timestamp":1728950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Buffalo\u2019s CTSI","award":["KL2 BTC award"],"award-info":[{"award-number":["KL2 BTC award"]}]},{"name":"University of Buffalo\u2019s CTSI","award":["P30 CA016056"],"award-info":[{"award-number":["P30 CA016056"]}]},{"name":"Data Bank and BioRepository (DBBR)","award":["KL2 BTC award"],"award-info":[{"award-number":["KL2 BTC award"]}]},{"name":"Data Bank and BioRepository (DBBR)","award":["P30 CA016056"],"award-info":[{"award-number":["P30 CA016056"]}]},{"name":"National Cancer Institute","award":["KL2 BTC award"],"award-info":[{"award-number":["KL2 BTC award"]}]},{"name":"National Cancer Institute","award":["P30 CA016056"],"award-info":[{"award-number":["P30 CA016056"]}]},{"name":"Roswell Park Cancer Institute Cancer Center Support Grant","award":["KL2 BTC award"],"award-info":[{"award-number":["KL2 BTC award"]}]},{"name":"Roswell Park Cancer Institute Cancer Center Support Grant","award":["P30 CA016056"],"award-info":[{"award-number":["P30 CA016056"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cancer cohorts are now known to be associated with increased rates of clonal hematopoiesis (CH). We sort to characterize the hematopoietic compartment of patients with melanoma and non-small cell lung cancer (NSCLC) given our recent population level analysis reporting evolving rates of secondary leukemias. The advent of immune checkpoint blockade (ICB) has dramatically changed our understanding of cancer biology and has altered the standards of care for patients. However, the impact of ICB on hematopoietic myeloid clonal expansion remains to be determined. We studied if exposure to ICB therapy affects hematopoietic clonal architecture and if their evolution contributed to altered hematopoiesis. Blood samples from patients with melanoma and NSCLC (n = 142) demonstrated a high prevalence of CH. Serial samples (or post ICB exposure samples; n = 25) were evaluated in melanoma and NSCLC patients. Error-corrected sequencing of a targeted panel of genes recurrently mutated in CH was performed on peripheral blood genomic DNA. In serial sample analysis, we observed that mutations in DNMT3A and TET2 increased in size with longer ICB exposures in the melanoma cohort. We also noted that patients with larger size DNMT3A mutations with further post ICB clone size expansion had longer durations of ICB exposure. All serial samples in this cohort showed a statistically significant change in VAF from baseline. In the serial sample analysis of NSCLC patients, we observed similar epigenetic expansion, although not statistically significant. Our study generates a hypothesis for two important questions: (a) Can DNMT3A or TET2 CH serve as predictors of a response to ICB therapy and serve as a novel biomarker of response to ICB therapy? (b) As ICB-exposed patients continue to live longer, the myeloid clonal expansion may portend an increased risk for subsequent myeloid malignancy development. Until now, the selective pressure of ICB\/T-cell activating therapies on hematopoietic stem cells were less known and we report preliminary evidence of clonal expansion in epigenetic modifier genes (also referred to as inflammatory CH genes).<\/jats:p>","DOI":"10.3390\/ijms252011049","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T08:09:08Z","timestamp":1728979748000},"page":"11049","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Immune Checkpoint Inhibitor Therapy and Associations with Clonal Hematopoiesis"],"prefix":"10.3390","volume":"25","author":[{"given":"Abhay","family":"Singh","sequence":"first","affiliation":[{"name":"Leukemia and Myeloid Disorders Program, Cleveland Clinic, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria Mencia","family":"Trinchant","sequence":"additional","affiliation":[{"name":"Division of Medicine, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5631-1164","authenticated-orcid":false,"given":"Rahul","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Anne Arundel Medical Center, Annapolis, MD 21401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirti","family":"Arora","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cleveland Clinic Akron General Hospital, Akron, OH 44307, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9440-0644","authenticated-orcid":false,"given":"Smit","family":"Mehta","sequence":"additional","affiliation":[{"name":"Leukemia and Myeloid Disorders Program, Cleveland Clinic, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodora","family":"Kuzmanovic","sequence":"additional","affiliation":[{"name":"Leukemia and Myeloid Disorders Program, Cleveland Clinic, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maedeh","family":"Zokaei Nikoo","sequence":"additional","affiliation":[{"name":"University Hospitals, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8999-9532","authenticated-orcid":false,"given":"Inderpreet","family":"Singh","sequence":"additional","affiliation":[{"name":"Upstate Community Hospital, SUNY Upstate Medical University, Syracuse, NY 13210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda C.","family":"Przespolewski","sequence":"additional","affiliation":[{"name":"Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh","family":"Swaminathan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8132-7069","authenticated-orcid":false,"given":"Marc S.","family":"Ernstoff","sequence":"additional","affiliation":[{"name":"Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace K.","family":"Dy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lunbiao","family":"Yan","sequence":"additional","affiliation":[{"name":"Division of Medicine, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4680-0321","authenticated-orcid":false,"given":"Eti","family":"Sinha","sequence":"additional","affiliation":[{"name":"Division of Medicine, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shruti","family":"Sharma","sequence":"additional","affiliation":[{"name":"Upstate Community Hospital, SUNY Upstate Medical University, Syracuse, NY 13210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duane C.","family":"Hassane","sequence":"additional","affiliation":[{"name":"Division of Medicine, Weill Cornell Medical College, New York, NY 10065, USA"},{"name":"Tempus Labs, Inc., Chicago, IL 60654, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Griffiths","sequence":"additional","affiliation":[{"name":"Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8644-0968","authenticated-orcid":false,"given":"Eunice","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica L.","family":"Guzman","sequence":"additional","affiliation":[{"name":"Division of Medicine, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4216-1414","authenticated-orcid":false,"given":"Swapna","family":"Thota","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2100309","DOI":"10.1200\/PO.21.00309","article-title":"Mutant PPM1D- and TP53-Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy","volume":"6","author":"Singh","year":"2022","journal-title":"JCO Precis. 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