Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm
Guangyao Kong, … , James C. Mulloy, Jing Zhang
Guangyao Kong, … , James C. Mulloy, Jing Zhang
Published May 8, 2014
Citation Information: J Clin Invest. 2014;124(6):2762-2773. https://doi.org/10.1172/JCI74182.
View: Text | PDF
Research Article Hematology Article has an altmetric score of 15

Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm

  • Text
  • PDF
Abstract

Overactive RAS signaling is prevalent in juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myelomonocytic leukemia (MP-CMML) in humans, and both are refractory to conventional chemotherapy. Conditional activation of a constitutively active oncogenic Nras (NrasG12D/G12D) in murine hematopoietic cells promotes an acute myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-CMML. We found that NrasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML–initiating cells, show strong hyperactivation of ERK1/2, promoting hyperproliferation and depletion of HSCs and expansion of downstream progenitors. Inhibition of the MEK pathway alone prolonged the presence of NrasG12D/G12D-expressing HSCs but failed to restore their proper function. Consequently, approximately 60% of NrasG12D/G12D mice treated with MEK inhibitor alone died within 20 weeks, and the remaining animals continued to display JMML/MP-CMML–like phenotypes. In contrast, combined inhibition of MEK and JAK/STAT signaling, which is commonly hyperactivated in human and mouse CMML, potently inhibited human and mouse CMML cell growth in vitro, rescued mutant NrasG12D/G12D-expressing HSC function in vivo, and promoted long-term survival without evident disease manifestation in NrasG12D/G12D animals. These results provide a strong rationale for further exploration of combined targeting of MEK/ERK and JAK/STAT in treating patients with JMML and MP-CMML.

Authors

Guangyao Kong, Mark Wunderlich, David Yang, Erik A. Ranheim, Ken H. Young, Jinyong Wang, Yuan-I Chang, Juan Du, Yangang Liu, Sin Ruow Tey, Xinmin Zhang, Mark Juckett, Ryan Mattison, Alisa Damnernsawad, Jingfang Zhang, James C. Mulloy, Jing Zhang

×

Figure 2

NrasG12D/G12D hyperactivates ERK1/2 in HSCs, and downregulation of MEK/ERK signaling rescues NrasG12D/G12D HSC exhaustion.

Options: View larger image (or click on image) Download as PowerPoint

NrasG12D/G12D hyperactivates ERK1/2 in HSCs, and downregulation of MEK/...
Control and NrasG12D/G12D mice were treated with pI-pC and sacrificed on day 12. (A and B) CD150+CD41– cells (enriched for HSCs) and CD150–CD41– cells (enriched for MPPs) were sorted from Sca1+-enriched total BM cells. Sorted cells were serum and cytokine starved for 30 minutes at 37°C (A). IL-3 stimulation was performed for 10 minutes at 37°C after starvation (B). Levels of pERK1/2 and pAKT were measured using phosphospecific flow cytometry. HSCs (defined as [Lin CD48]–/locKit+ cells from sorted CD150+CD41– cells) and MPPs (defined as [Lin CD48]–/locKit+ cells from sorted CD150–CD41– cells) were gated for data analysis. To quantify the activation of ERK1/2, median intensities of pERK1/2 at different IL-3 concentrations are shown relative to the respective control cells at 0 ng/ml (assigned as 1). (C) Quantification of c-Myc and cell senescence–related genes in control and NrasG12D/G12D HSCs using qRT-PCR. (D) Quantification of BM spleen HSCs from control and NrasG12D/G12D mice treated with vehicle or AZD6244 for 7 days. (E) Single NrasG12D/G12D HSC genotyping after AZD6244 treatment. Data are mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 1 news outlets
Blogged by 1
Posted by 2 X users
26 readers on Mendeley
See more details