H Syndrome and Histiocytosis: A Rare Genetic Disorder Reveals an Unexpected Pathway for MAPK Activation

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Ruth Shiloh, Schneider Medical Center​

 

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germline loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism leading to histiocytosis for these patients remained unclear. Through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we revealed the molecular pathway leading to histiocytosis and inflammation in this genetic disorder, showing that loss-of-function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.