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

1. Driver mutations were traced to myeloid and lymphoid lineage cells in patients with single-system histiocytosis

2. Recurrent xanthogranulomas may arise through 2^nd hits acquired by the progeny of long-lived BRAF- or KRAS-mutated multipotent progenitors

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 PCR assays specific for BRAF, MAP2K1 or KRAS alterations detected in histiocytosis lesions, we could trace the same driver mutation to circulating blood cells in 13/14 patients. In 9/13 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 KRAS or BRAF mutation in xanthogranulomas that developed up to 25 years apart. As proof of concept, we traced the driver mutation to CD34⁺ progenitors in 1 of the 3 patients. Distinct secondary mutations in either KRAS, BRAF or ARAF 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 KRAS mutation were identified in the unifocal Langerhans cell sarcoma lesion of the only patient without circulating mutated cells. Together, these data point towards multipotent hematopoietic progenitors as the cell-of-origin of both single-system and multisystem histiocytosis.