RT Journal Article
SR Electronic
T1 DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.27.449656
DO 10.1101/2021.06.27.449656
A1 Tim Kong
A1 Angelo Brunelli Albertoni Laranjeira
A1 Kangning Yang
A1 Daniel A. C. Fisher
A1 LaYow Yu
A1 Anthony Z Wang
A1 Marianna Ruzinova
A1 Jared S. Fowles
A1 Maggie J. Allen
A1 Hamza Celik
A1 Grant A. Challen
A1 Sidong Huang
A1 Stephen T. Oh
YR 2021
UL http://biorxiv.org/content/early/2021/07/02/2021.06.27.449656.abstract
AB Chronic 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 bulk transcriptome profiling accompanied by single cell RNA-sequencing on CD34+ stem/progenitor cells from serial patient samples obtained at the chronic MPN and sAML phases, and identified aberrantly increased expression of dual-specificity phosphatase 6 (DUSP6) underlying disease transformation. Genetic and pharmacologic targeting of DUSP6 led to inhibition of S6 and JAK/STAT signaling, resulting in potent suppression of cell proliferation, while also reducing inflammatory cytokine production in primary samples. Furthermore, ectopic DUSP6 expression augmented proliferation and mediated JAK2 inhibitor resistance, while DUSP6 inhibition reduced colony-forming potential of JAK2 inhibitor-persistent patient cells. Mechanistically, DUSP6 perturbation dampened S6 signaling via inhibition of RSK1, which we identified as a second indispensable candidate associated with poor clinical outcome. Lastly, DUSP6 inhibition potently suppressed disease development across Jak2 V617F and MPL W515L MPN mouse models, and sAML patient-derived xenografts. These findings underscore DUSP6 in driving disease transformation and therapeutic resistance, and highlight the DUSP6-RSK1 axis as a novel, druggable pathway in myeloid malignancies.Competing Interest StatementS.T.O. has served as a consultant for Kartos Therapeutics, CTI BioPharma, Celgene/Bristol Myers Squibb, Disc Medicine, Blueprint Medicines, PharmaEssentia, Constellation, Geron, Abbvie, Sierra Oncology, and Incyte. All other authors disclose no competing interests.