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

Sime Brkic,Matthias S Dettmer,Gregor Hutter,Dimitrios Tsakiris,Alice Santopolo,Sara C Meyer,Jakob R Passweg,Katharina Leonards,Simona Stivala,Stefan Dirnhofer,Sarah Jungius,Jakub Szybinski,Benjamin G Neel,Heidi E L Lischer,Ross L Levine

doi:10.1038/s41375-021-01391-2

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.

Highlights

Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders characterized by excessive output of mature myeloid cells and inherent risk for leukemic transformation [1]
Genetic targeting of ERK1/2 mitigates the MPN phenotype and impairs the fitness of the Jak2V617F clone To assess the role of ERK1/2 for hematopoiesis in Jak2V617F MPN settings, we crossed conditional Jak2V617F knock-in [23] to Erk1−/ −Erk2fl/fl mice [21] expressing Mx-1-Cre recombinase
ERK1/2 deficiency moderated the erythrocytosis of Jak2V617F mice and mitigated additional MPN features, leukocytosis, splenomegaly and bone marrow (BM) fibrosis

Summary

Introduction

Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders characterized by excessive output of mature myeloid cells and inherent risk for leukemic transformation [1]. MPN subtypes show distinct clinical phenotypes; polycythemia vera (PV) primarily characterized by erythrocytosis, essential thrombocythemia (ET) featuring thrombocytosis, and myelofibrosis (MF) typified by progressive bone marrow (BM) fibrosis inducing cytopenias [2]. These MPN subsets share dysregulated JAK2 signaling [3] constitutively activated by somatic mutations in JAK2, thrombopoietin receptor MPL or the chaperone calreticulin (CALR) [4]. Disease-modifying activity of clinical JAK2 inhibitors has remained modest [6]

Methods

Results

Conclusion