DUSP6 Mediates Resistance to JAK2 Inhibition and Drives Leukemic Progression

Overview

Journal Nat Cancer

Specialty Oncology

Date 2022 Dec 29

PMID 36581736

Authors

Tim Kong

Angelo B A Laranjeira

Kangning Yang

Daniel A C Fisher

LaYow Yu

Laure Poittevin De La Fregonniere

Anthony Z Wang

Marianna B Ruzinova

Jared S Fowles

Mary C Fulbright

Maggie J Cox

Hamza Celik

Grant A Challen

Sidong Huang

Stephen T Oh

Affiliations

Soon will be listed here.

Abstract

Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells, identifying aberrantly increased expression of DUSP6 underlying disease transformation. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling while also reducing inflammatory cytokine production. DUSP6 perturbation further inhibited ribosomal S6 kinase (RSK)1, which we identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 mediated JAK2-inhibitor resistance and exacerbated disease severity in patient-derived xenograft (PDX) models. Contrastingly, DUSP6 inhibition potently suppressed disease development across Jak2 and MPL MPN mouse models and sAML PDXs without inducing toxicity in healthy controls. These findings underscore DUSP6 in driving disease transformation and highlight the DUSP6-RSK1 axis as a vulnerable, druggable pathway in myeloid malignancies.

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