ArticleOncotarget2018
Mechanisms for mTORC1 activation and synergistic induction of apoptosis by ruxolitinib and BH3 mimetics or autophagy inhibitors in JAK2-V617F-expressing leukemic cells including newly established PVTL-2.
Article in Oncotarget, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 25 citations in OpenAlex.
- Programmable DNA Assemblies Reconstitute Supramolecular Protein Function.bioRxiv : the preprint server for biology · 2026Article
- Review
- Ruxolitinib reduces macrophage pyroptosis in aplastic anaemia.Clinical and experimental medicine · 2026Article
- Dibenzo [a, c] phenazin-11-yl(phenyl) methanone (SBLJ23), a novel selective inhibitor targeting JAK2Oncology research · 2025Article
- Ruxolitinib-loaded poly-ɛ-caprolactone (PCL) nanoparticles inhibit JAK2/STAT5 signaling in BT474 breast cancer cells by downregulating Bcl-2 and Mcl-1.Molecular biology reports · 2024Article
- Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity.Journal of clinical medicine · 2023Article
- Targeting PP2A-dependent autophagy enhances sensitivity to ruxolitinib in JAK2Blood cancer journal · 2023Article
- Autophagy and SARS-CoV-2-Old Players in New Games.International journal of molecular sciences · 2023Review
- The role of autophagy in controlling SARS-CoV-2 infection: An overview on virophagy-mediated molecular drug targets.Cell biology international · 2021Review
- Article
- Targeting Multiple Signal Transduction Pathways of SARS-CoV-2: Approaches to COVID-19 Therapeutic Candidates.Molecules (Basel, Switzerland) · 2021Review
- The potential of proliferative and apoptotic parameters in clinical flow cytometry of myeloid malignancies.Blood advances · 2021Review
- Somatically acquired mutations in primary myelofibrosis: A case report and meta-analysis.Experimental and therapeutic medicine · 2021Article
- Autophagy and SARS-CoV-2 infection: Apossible smart targeting of the autophagy pathway.Virulence · 2020Article
- Finding a Jill for JAK: Assessing Past, Present, and Future JAK Inhibitor Combination Approaches in Myelofibrosis.Cancers · 2020Review
- The potential of JAK/STAT pathway inhibition by ruxolitinib in the treatment of COVID-19.Cytokine & growth factor reviews · 2020Review
- Article
- The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN.Blood advances · 2019Article
- Article
- Curcumin induces apoptosis in JAK2-mutated cells by the inhibition of JAK2/STAT and mTORC1 pathways.Journal of cellular and molecular medicine · 2019Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The activated JAK2-V617F mutant is very frequently found in myeloproliferative neoplasms (MPNs), and its inhibitor ruxolitinib has been in clinical use, albeit with limited efficacies. Here, we examine the signaling mechanisms from JAK2-V617F and responses to ruxolitinib in JAK2-V617F-positive leukemic cell lines, including PVTL-2, newly established from a patient with post-MPN secondary acute myeloid leukemia, and the widely used model cell line HEL. We have found that ruxolitinib downregulated the mTORC1/S6K/4EBP1 pathway at least partly through inhibition of the STAT5/Pim-2 pathway with concomitant downregulation of c-Myc, MCL-1, and BCL-xL as well as induction of autophagy in these cells. Ruxolitinib very efficiently inhibited proliferation but only modestly induced apoptosis. However, inhibition of BCL-xL/BCL-2 by the BH3 mimetics ABT-737 and navitoclax or BCL-xL by A-1331852 induced caspase-dependent apoptosis involving activation of Bak and Bax synergistically with ruxolitinib in HEL cells. On the other hand, the putative pan-BH3 mimetic obatoclax as well as chloroquine and bafilomycin A1 inhibited autophagy at its late stage and induced apoptosis in PVTL-2 cells synergistically with ruxolitinib. The present study suggests that autophagy as well as the anti-apoptotic BCL-2 family members, regulated at least partly by the mTORC1 pathway downstream of STAT5/Pim-2, protects JAK2-V617F-positive leukemic cells from ruxolitinib-induced apoptosis depending on cell types and may contribute to development of new strategies against JAK2-V617F-positive neoplasms.
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