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DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression.
Kong, Tim; Laranjeira, Angelo B A; Yang, Kangning; Fisher, Daniel A C; Yu, LaYow; Poittevin De La Frégonnière, Laure; Wang, Anthony Z; Ruzinova, Marianna B; Fowles, Jared S; Fulbright, Mary C; Cox, Maggie J; Celik, Hamza; Challen, Grant A; Huang, Sidong; Oh, Stephen T.
Afiliación
  • Kong T; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Laranjeira ABA; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Yang K; Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
  • Fisher DAC; Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
  • Yu L; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Poittevin De La Frégonnière L; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Wang AZ; Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
  • Ruzinova MB; Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
  • Fowles JS; Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.
  • Fulbright MC; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • Cox MJ; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Celik H; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Challen GA; Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Huang S; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Oh ST; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Nat Cancer ; 4(1): 108-127, 2023 01.
Article en En | MEDLINE | ID: mdl-36581736
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 Jak2V617F and MPLW515L 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Trastornos Mieloproliferativos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Cancer Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Trastornos Mieloproliferativos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Cancer Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido