The role of the JunD-RhoH axis in the pathogenesis of hairy cell leukemia and its ability to identify existing therapeutics that could be repurposed to treat relapsed or refractory disease.

Abstract

Hairy cell leukemia (HCL) is an indolent malignancy of mature B-lymphocytes. While existing front-line therapies achieve excellent initial results, a significant number of patients relapse and become increasingly treatment resistant. A major molecular driver of HCL is aberrant interlocking expression of the transcription factor JunD and the intracellular signaling molecule RhoH. Here we discuss the molecular basis of how the JunD-RhoH axis contributes to HCL pathogenesis. We also discuss how leveraging the JunD-RhoH axis identifies CD23, CD38, CD66a, CD115, CD269, integrin β7, and MET as new potential therapeutic targets. Critically, preclinical studies have already demonstrated that targeting CD38 with isatuximab effectively treats preexisiting HCL. Isatuximab and therapeutics directed against each of the other six new HCL targets are currently in clinical use to treat other disorders. Consequently, leveraging the JunD-RhoH axis has identified a battery of therapies that could be repurposed as new means of treating relapsed or refractory HCL.