Driver mutations in myeloid and lymphoid cells point to multipotent progenitor origin of diverse histiocytic neoplasms

{"title":"Driver mutations in myeloid and lymphoid cells point to multipotent progenitor origin of diverse histiocytic neoplasms","authors":"Astrid G. S. van Halteren ∗ ,&nbsp;Paul G. Kemps ∗ ,&nbsp;Jelske Forma-Borst ,&nbsp;Yanling Xiao ,&nbsp;Maud A. J. I. van den Oetelaar ,&nbsp;Nina U. Gelineau ,&nbsp;Robert M. Verdijk ,&nbsp;Lydia E. Vos ,&nbsp;Koen D. Quint ,&nbsp;Cor van den Bos ,&nbsp;Eli L. Diamond † ,&nbsp;Jan A. M. van Laar †","doi":"10.1016/j.bneo.2025.100074","DOIUrl":null,"url":null,"abstract":"<div><h3>Abstract</h3><div>Histiocytic neoplasms are rare myeloid diseases characterized by MAPK pathway–activating genetic alterations. We investigated their hematopoietic origin, with a focus on non-Langerhans cell histiocytoses. Using droplet digital polymerase chain reaction assays specific for <em>BRAF</em>, <em>MAP2K1</em>, or <em>KRAS</em> alterations detected in histiocytosis lesions, we could trace the same driver mutation to circulating blood cells in 13 of 14 patients. In 9 of 13 patients, the mutations were detected in circulating lymphoid cells, indicating that multipotent progenitors probably acquired these alterations. The 9 patients included 5 adults with single-system disease, including 3 with recurrent cutaneous xanthogranulomas. The presence of long-lived mutated progenitor cells in these 3 patients was supported by the detection of the same <em>KRAS</em> or <em>BRAF</em> mutation in xanthogranulomas that developed up to 25 years apart. As proof of concept, we traced the driver mutation to circulating CD34⁺ progenitors in 1 of the 3 patients. Distinct secondary mutations in either <em>KRAS</em>, <em>BRAF</em>, or <em>ARAF</em> were identified in separate xanthogranulomas from the same patient, indicating a 2-hit mutational process underlying the formation of these recurrent lesions. Finally, histiocytes and B cells harboring the same <em>KRAS</em> mutation were identified in the unifocal Langerhans cell sarcoma lesion of the only patient without circulating mutated cells. Together, these data point toward multipotent hematopoietic progenitors as the cell of origin of both single-system and multisystem histiocytoses.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 2","pages":"Article 100074"},"PeriodicalIF":0.0000,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Neoplasia","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2950328025000093","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}