Myeloproliferative neoplasms (MPN) show dysregulated JAK2 signaling. JAK2 inhibitors provide clinical benefits, but compensatory activation of MAPK pathway signaling impedes efficacy. We hypothesized that dual targeting of JAK2 and ERK1/2 could enhance clone control and therapeutic efficacy. We employed genetic and pharmacologic targeting of ERK1/2 in Jak2V617F MPN mice, cells and patient clinical isolates. Competitive transplantations of Jak2V617F vs. wild-type bone marrow (BM) showed that ERK1/2 deficiency in hematopoiesis mitigated MPN features and reduced the Jak2V617F clone in blood and hematopoietic progenitor compartments. ERK1/2 ablation combined with JAK2 inhibition suppressed MAPK transcriptional programs, normalized cytoses and promoted clone control suggesting dual JAK2/ERK1/2 targeting as enhanced corrective approach. Combined pharmacologic JAK2/ERK1/2 inhibition with ruxolitinib and ERK inhibitors reduced proliferation of Jak2V617F cells and corrected erythrocytosis and splenomegaly of Jak2V617F MPN mice. Longer-term treatment was able to induce clone reductions. BM fibrosis was significantly decreased in MPLW515L-driven MPN to an extent not seen with JAK2 inhibitor monotherapy. Colony formation from JAK2V617F patients’ CD34+ blood and BM was dose-dependently inhibited by combined JAK2/ERK1/2 inhibition in PV, ET, and MF subsets. Overall, we observed that dual targeting of JAK2 and ERK1/2 was able to enhance therapeutic efficacy suggesting a novel treatment approach for MPN.

Background:Myeloproliferative neoplasms (MPN) are hematologic malignancies that present with excessive production of mature myeloid blood cells. MPN are characterized by somatic mutations in JAK2, CALR or MPL, which result in constitutive activation of JAK2 signaling including STAT3/5, MAPK and PI3K/Akt pathways. JAK2 inhibitors like ruxolitinib effectively inhibit the JAK-STAT axis, but signaling via the MAPK pathway remains activated in vivo, thus limiting therapeutic effects. SHP2, Gab1 and Grb2 have been implicated in the signal transduction from JAK2 to the MAPK pathway, but the molecular connection is not fully clarified. Due to its important function in hematopoiesis, SHP2 is of special interest in an MPN setting.