Work

DUSP1 is a key driver of disease persistence and potential therapeutic target in hairy cell leukemia

Year: 2026

Type: article

Abstract: ABSTRACT: Classic hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder characterized by the driver mutation BRAF V600E. Standard treatment with purine analogs (eg, cladribine) induces long-term remissions, but up to 25% of patients relapse early. Even when targeting BRAF V600E, residual HCL cells frequently persist in the bone marrow (BM). To identify additional biological alterations contributing to HCL persistence, we performed single-cell RNA sequencing of sorted primary HCL cells from long-term vs short-term cladribine responders (ST-R; >10 vs ≤3 years of progression-free survival) at diagnosis and from ST-R at diagnosis vs relapse. We identified a distinct HCL subcluster characterized by increased DUSP1, FOS, and JUND expression that was detected in all patients and persisted or even expanded at relapse. Cancer pathway analysis suggested enhanced tumor microenvironment dependence, as reflected by suppression of the p38 mitogen-activated protein kinase pathway. In the absence of a suitable BRAF V600E-mutated HCL cell line, we validated HAIR-M cells (BRAF D594E) as a bona fide experimental HCL model. The activating BRAF D594E mutation mimics V600E-induced downstream signaling that can be effectively targeted by BRAF inhibitors (BRAFi). HAIR-M coculture with BM stromal cells (BMSC) strongly induced DUSP1 and was accompanied by protection from BRAFi-induced HAIR-M apoptosis. The functional importance of DUSP1 was corroborated by showing that BMSC-induced protection from cell death could be overcome by DUSP1 inhibition. Our results may set the stage for future clinical testing of DUSP1 inhibition to eliminate minimal residual disease and prevent relapse in HCL.

Source: Blood Advances

DOI: 10.1182/bloodadvances.2025019057