@article{c5772939dadf495ab000f9c78e67d783,
title = "DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression",
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 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.",
author = "Tim Kong and Laranjeira, {Angelo B.A.} and Kangning Yang and Fisher, {Daniel A.C.} and Yu, {La Yow} and {Poittevin De La Fr{\'e}gonni{\`e}re}, Laure and Wang, {Anthony Z.} and Ruzinova, {Marianna B.} and Fowles, {Jared S.} and Fulbright, {Mary C.} and Cox, {Maggie J.} and Hamza Celik and Challen, {Grant A.} and Sidong Huang and Oh, {Stephen T.}",
note = "Funding Information: This work was supported by NIH grants R01HL134952 (S.T.O.), R01HL147978 (G.A.C.) and T32HL007088 (J.S.F.) and by Canadian Institutes of Health Research grants PJT-156233 (S.H.) and PJT-438303 (S.H.). Additional support was provided by the Leukemia and Lymphoma Society Translational Research Program (S.T.O.), the MPN Research Foundation (S.T.O.), the When Everyone Survives Foundation (S.T.O.), the Edward P. Evans Foundation (G.A.C.), the Gabrielle{\textquoteright}s Angel Foundation (G.A.C.), a Canderel Rising Star Summer Studentship (K.Y.) and a Canadian Research Chair in Functional Genomics (S.H.). G.A.C. is a scholar of the Leukemia and Lymphoma Society. Technical support was provided by the Alvin J. Siteman Cancer Center Tissue Procurement Core Facility, the Biostatistics Shared Resource, the Flow Cytometry Core, the Barnes-Jewish Hospital, the Institute of Clinical and Translational Sciences and the Immunomonitoring Laboratory, which are supported by an NCATS Clinical and Translational Sciences Award (UL1 TR002345) and NCI Cancer Center Support Grant P30CA91842. Additional support was provided by the Barnard Cancer Institute. The Immunomonitoring Laboratory is also supported by the Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs. We thank D. Bender, R. Lin and K. Link for assistance with mass cytometry experiments. We are grateful to A. Mullally (DFCI) for providing Jak2 knockin mice and to R. Levine (MSKCC) for providing the MPL retroviral construct. We thank M. Fulbright for assistance with mouse colony management. We thank T. Ley for sharing TCGA LAML data. We thank F. Gao for assistance with biostatistical analysis. We thank A. Vogt for helpful discussions related to BCI. We thank the Genetic Perturbation Service of the Goodman Cancer Research Centre at McGill University for access to and preparation of functional genetic tools. V617F W515L Funding Information: This work was supported by NIH grants R01HL134952 (S.T.O.), R01HL147978 (G.A.C.) and T32HL007088 (J.S.F.) and by Canadian Institutes of Health Research grants PJT-156233 (S.H.) and PJT-438303 (S.H.). Additional support was provided by the Leukemia and Lymphoma Society Translational Research Program (S.T.O.), the MPN Research Foundation (S.T.O.), the When Everyone Survives Foundation (S.T.O.), the Edward P. Evans Foundation (G.A.C.), the Gabrielle{\textquoteright}s Angel Foundation (G.A.C.), a Canderel Rising Star Summer Studentship (K.Y.) and a Canadian Research Chair in Functional Genomics (S.H.). G.A.C. is a scholar of the Leukemia and Lymphoma Society. Technical support was provided by the Alvin J. Siteman Cancer Center Tissue Procurement Core Facility, the Biostatistics Shared Resource, the Flow Cytometry Core, the Barnes-Jewish Hospital, the Institute of Clinical and Translational Sciences and the Immunomonitoring Laboratory, which are supported by an NCATS Clinical and Translational Sciences Award (UL1 TR002345) and NCI Cancer Center Support Grant P30CA91842. Additional support was provided by the Barnard Cancer Institute. The Immunomonitoring Laboratory is also supported by the Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs. We thank D. Bender, R. Lin and K. Link for assistance with mass cytometry experiments. We are grateful to A. Mullally (DFCI) for providing Jak2V617Fknockin mice and to R. Levine (MSKCC) for providing the MPLW515Lretroviral construct. We thank M. Fulbright for assistance with mouse colony management. We thank T. Ley for sharing TCGA LAML data. We thank F. Gao for assistance with biostatistical analysis. We thank A. Vogt for helpful discussions related to BCI. We thank the Genetic Perturbation Service of the Goodman Cancer Research Centre at McGill University for access to and preparation of functional genetic tools. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2023",
month = jan,
doi = "10.1038/s43018-022-00486-8",
language = "English",
volume = "4",
pages = "108--127",
journal = "Nature Cancer",
issn = "2662-1347",
number = "1",
}