Despite the impressive response to tyrosine kinase inhibitor (TKI) therapy in the clinic as an anti-cancer treatment, it is not curative. Even the most potent kinase inhibitors are ineffective against a small population of cancer cells, which are insensitive to treatment; manifesting as minimal residual disease (MRD). Likewise, myeloproliferative disorders treated with Jak2 inhibitors show intrinsic resistance to TKI treatment . Failure eradicate the persistent cells them leads to post-therapy relapse. Therapeutic response to TKI is mediated by oncogene-addiction; however, the molecular mechanisms governing TKI-induced cell death in the context of oncogene-addiction is not clearly understood. We find that MAPK phosphatase, Dusp1, is a critical mediator of oncogene-addiction in MPD driven by mutations in JAK2, MPL and CSF3R. Overexpression of Dusp1 in MPDs abrogates oncogene addiction and ablates TKI response. Both genetic and pharmacological inhibition of Dusp1 is synthetic lethal to Jak2-V761F and CSF3R-T618I driven MPDs. The proposed research will address the sensitivity of murine-model of MPD leukemia initiating cells and primary patient specimens to disrupting Dusp1 activity alone and in the context of TKI therapy. In addition, we propose to develop specific and potent Dusp1 inhibitor using structure function studies for clinical application. Our results should accelerate development of a curative therapy for MPDs.