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

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)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Tschanz-Lischer, Heidi Erika Lisa and Dettmer, Matthias

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1476-5551

Publisher:

Springer Nature

Language:

English

Submitter:

Andrea Stettler

Date Deposited:

19 Nov 2021 08:52

Last Modified:

19 Nov 2021 08:58

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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