ArticleThe Journal of clinical investigation2019
Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
75 citing papers in PubMed, 125 citations in OpenAlex.
- DUSP13 promotes prostate cancer progression by regulating the ERK1/2 pathway.Translational andrology and urology · 2026Article
- Physiological MplW514L expression in hematopoietic stem cell causes an essential thrombocythemia and progressive myelofibrosis.The Journal of clinical investigation · 2026Article
- Exploring the mechanism of Dieda Qili Tablet on fracture healing based on network pharmacology combined with machine learning models.Scientific reports · 2026Article
- Article
- BCL-XL drives fibrotic and leukemic progression in myeloproliferative neoplasms.Frontiers in immunology · 2026Article
- MarkerPredict: predicting clinically relevant predictive biomarkers with machine learning.NPJ systems biology and applications · 2025Article
- Combined MEK and JAK inhibition reduces osteopontin plasma level and bone marrow fibrosis in a myelofibrosis mouse model.Blood cancer journal · 2025Article
- Synergistic effects of deleting the tyrosine phosphatases Shp1 and Shp2 on megakaryopoiesis and thrombopoiesis in mice.bioRxiv : the preprint server for biology · 2025Article
- Efficacy of a novel BCL-xL degrader, DT2216, in preclinical models of JAK2-mutated post-MPN AML.Blood · 2025Article
- JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms.Nature communications · 2025Article
- Malignant JAK-signaling: at the interface of inflammation and malignant transformation.Leukemia · 2025Review
- Paediatric bone marrow mesenchymal stem cells support acute myeloid leukaemia cell survival and enhance chemoresistance via contact-independent mechanism.British journal of haematology · 2025Article
- Case Report: Myelodysplastic/myeloproliferative neoplasm with concurrent SF3B1, ASXL1, JAK2 and CBL mutations and <15% bone marrow ringed sideroblasts.Frontiers in oncology · 2025Article
- JAK Inhibitors for Myelofibrosis: Strengths and Limitations.Current hematologic malignancy reports · 2024Review
- Oncogenic Calreticulin Induces Immune Escape by Stimulating TGFβ Expression and Regulatory T-cell Expansion in the Bone Marrow Microenvironment.Cancer research · 2024Article
- Predicting Abrocitinib Efficacy at Week 12 Based on Clinical Response at Week 4: A Post Hoc Analysis of Four Randomized Studies in Moderate-to-Severe Atopic Dermatitis.Dermatology and therapy · 2024Article
- SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms.American journal of hematology · 2024Article
- Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms.Cancer discovery · 2024Article
- RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives.Blood cancer journal · 2024Review
- Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
15 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 5 institutions in 2 countries.
Funding
Abstract
Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT, and MEK/ERK signaling. However, the therapeutic efficacy of current JAK2 inhibitors is limited. We investigated the role of MEK/ERK signaling in MPN cell survival in the setting of JAK inhibition. Type I and II JAK2 inhibition suppressed MEK/ERK activation in MPN cell lines in vitro, but not in Jak2V617F and MPLW515L mouse models in vivo. JAK2 inhibition ex vivo inhibited MEK/ERK signaling, suggesting that cell-extrinsic factors maintain ERK activation in vivo. We identified PDGFRα as an activated kinase that remains activated upon JAK2 inhibition in vivo, and PDGF-AA/PDGF-BB production persisted in the setting of JAK inhibition. PDGF-BB maintained ERK activation in the presence of ruxolitinib, consistent with its function as a ligand-induced bypass for ERK activation. Combined JAK/MEK inhibition suppressed MEK/ERK activation in Jak2V617F and MPLW515L mice with increased efficacy and reversal of fibrosis to an extent not seen with JAK inhibitors. This demonstrates that compensatory ERK activation limits the efficacy of JAK2 inhibition and dual JAK/MEK inhibition provides an opportunity for improved therapeutic efficacy in MPNs and in other malignancies driven by aberrant JAK-STAT signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.