Mutations in Receptor Tyrosine Kinases Drive Histiocytic Disorders

The development of histiocytoses, clonal hematopoietic disorders of unclear cellular origin, is poorly understood, and therapeutic targets have generally been limited to BRAF and MEK, two kinases thought to drive many of these disorders. In a genomic analysis of 270 patients with various histiocytoses, Durham, Rodrigo, Picarsic, and colleagues identified a previously unknown set of potential driver mutations in genes encoding receptor tyrosine kinases, including activating mutations in CSF1R (encoding CSF1R, also known as M-CSF) and rearrangements in RET and ALK. In one case, whole-exome sequencing of tissue samples from one-year-old monozygotic, monochorionic, diamniotic twins with the histiocytic disorder systemic juvenile xanthogranuloma revealed identical in-frame deletions in CSF1R in skin lesions, but not in blood or fingernails. The presence of identical CSF1R mutations in disease lesions but not blood or fingernails of the twins supports the idea that a CSF1R-mutant extra-embryonic yolk-sac precursor was the originator of the tumors. This finding aligns with the results of a recent mouse study and does not support the alternative explanation that the origin of the malignant clone was a bone marrow–derived myeloid cell that arose in one twin and spread to the other through vascular anastomoses. In addition to identifying a potential developmental origin for a histiocytic disorder, the group tested whether the presence of certain potential driver mutations was predictive of response to corresponding drugs. Notably, substantial and sustained responses were seen in patients positive for the BICD2–BRAF, KIF5B–ALK, or NCOA4–RET rearrangements treated with the MEK1/2 inhibitor trametinib, the ALK inhibitor crizotinib, or the RET inhibitor selpercatinib, respectively. These results highlight the potential value of genomic analysis in patients with treatment-refractory histiocytoses and provide preliminary evidence supporting treatments that may be of value in patient populations bearing specific types of mutations. Additionally, further investigation to determine whether the developmental origin of other histiocytic disorders matches that described here for systemic juvenile xanthogranuloma would be of interest.

Durham BH, Rodrigo EL, Picarsic J, Abramson D, Rotemberg V, De Munck S, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med 2019;25:1839–42.

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