Brkic, Sime; Stivala, Simona; Santopolo, Alice; Szybinski, Jakub; Jungius, Sarah; Passweg, Jakob R; Tsakiris, Dimitrios; Dirnhofer, Stefan; Hutter, Gregor; Leonards, Katharina; Lischer, Heidi E L; Dettmer, Matthias S; Neel, Benjamin G; Levine, Ross L; Meyer, Sara C (2021). Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy. Leukemia, 35(10), pp. 2875-2884. Springer Nature 10.1038/s41375-021-01391-2
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory 04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology 04 Faculty of Medicine > Service Sector > Institute of Pathology 08 Faculty of Science > Department of Biology > Bioinformatics and Computational Biology |
UniBE Contributor: |
Tschanz-Lischer, Heidi Erika Lisa, Dettmer, Matthias, Meyer, Sara Christina |
Subjects: |
600 Technology > 610 Medicine & health 500 Science > 570 Life sciences; biology |
ISSN: |
1476-5551 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Andrea Stettler |
Date Deposited: |
19 Nov 2021 08:52 |
Last Modified: |
14 Dec 2022 18:38 |
Publisher DOI: |
10.1038/s41375-021-01391-2 |
PubMed ID: |
34480104 |
BORIS DOI: |
10.48350/161377 |
URI: |
https://boris.unibe.ch/id/eprint/161377 |
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