Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy

Leukemia. 2021 Oct;35(10):2875-2884. doi: 10.1038/s41375-021-01391-2. Epub 2021 Sep 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Leukemic / drug effects*
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 1 / physiology
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 3 / physiology
  • Myeloproliferative Disorders / drug therapy*
  • Myeloproliferative Disorders / metabolism
  • Myeloproliferative Disorders / pathology
  • Nitriles / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology*
  • Pyrimidines / pharmacology*

Substances

  • Nitriles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • ruxolitinib
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Mapk1 protein, mouse
  • Mapk3 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3