Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • 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
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors
Ying Cheng, … , John K. Choi, Wei Tong
Ying Cheng, … , John K. Choi, Wei Tong
Published March 14, 2016
Citation Information: J Clin Invest. 2016;126(4):1267-1281. https://doi.org/10.1172/JCI81468.
View: Text | PDF
Research Article Oncology

LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors

  • Text
  • PDF
Abstract

Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk ALL commonly associated with alterations that affect the tyrosine kinase pathway, tumor suppressors, and lymphoid transcription factors. Loss-of-function mutations in the gene-encoding adaptor protein LNK (also known as SH2B3) are found in Ph-like ALLs; however, it is not clear how LNK regulates normal B cell development or promotes leukemogenesis. Here, we have shown that combined loss of Lnk and tumor suppressors Tp53 or Ink4a/Arf in mice triggers a highly aggressive and transplantable precursor B-ALL. Tp53–/–Lnk–/– B-ALLs displayed similar gene expression profiles to human Ph-like B-ALLs, supporting use of this model for preclinical and molecular studies. Preleukemic Tp53–/–Lnk–/– pro-B progenitors were hypersensitive to IL-7, exhibited marked self-renewal in vitro and in vivo, and were able to initiate B-ALL in transplant recipients. Mechanistically, we demonstrated that LNK regulates pro-B progenitor homeostasis by attenuating IL-7–stimuated JAK/STAT5 signaling via a direct interaction with phosphorylated JAK3. Moreover, JAK inhibitors were effective in prolonging survival of mice transplanted with Lnk–/–Tp53–/– leukemia. Additionally, synergistic administration of PI3K/mTOR and JAK inhibitors further abrogated leukemia development. Hence, our results suggest that LNK suppresses IL-7R/JAK/STAT signaling to restrict pro-/pre-B progenitor expansion and leukemia development, providing a pathogenic mechanism and a potential therapeutic approach for B-ALLs with LNK mutations.

Authors

Ying Cheng, Kudakwashe Chikwava, Chao Wu, Haibing Zhang, Anchit Bhagat, Dehua Pei, John K. Choi, Wei Tong

×

Figure 9

Synergistic inhibition of Lnk–/–p53–/– leukemic cell growth with JAK and PI3K/mTOR inhibitors.

Options: View larger image (or click on image) Download as PowerPoint
Synergistic inhibition of Lnk–/–p53–/– leukemic cell growth with JAK and...
(A) Lnk–/–p53–/– leukemic blasts show elevated basal activation of pAKT, pS6, and pERK. Representative phosphoflow shows the activation status of indicated proteins in BM B220loICμmed cells in comparison with leukemic cells after 1 hour of starvation. The dot plots show relative MFI of phosphoflow signals. n = 5–10. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed Student’s t test. n = 5–10 mice per group. (B) Growth response curves for B-ALL cells treated with various concentrations of JAK and PI3K inhibitors. Lnk–/–p53–/– leukemic blasts were cultured in liquid culture supplemented with SCF and IL-7 in the presence of different concentrations of inhibitors, as indicated. Live cell numbers after 3 days of culture were determined by MTT absorbance. Representative results from 3 independent B-ALLs. (C) WB analyses for effector proteins of the STAT5, ERK, and PI3K/AKT pathways. Lnk–/–p53–/– leukemic blasts were stimulated with SCF and IL-7 for 20 minutes in the absence or presence of pretreatment with different concentrations of inhibitors. Cells were lysed, and the protein lysates were subjected to WB analysis with indicated antibodies. (D) Cohort of mice transplanted with Lnk–/–p53–/– B-ALLs were treated either with vehicle alone, ruxolitinib (JAKi), BEZ (PI3Ki), or combined 12 days after transplant. Kaplan-Meier survival curves are shown. Log-rank t test, *P < 0.001; **P < 0.0001; drug treatment groups compared with vehicle group. #P < 0.01; ##P < 0.005, single drug treatment groups compared with combined drug treatment group. n = 7–9 mice per group. (E and F) Cohort of mice transplanted with Lnk–/–p53–/– B-ALLs were treated either with vehicle alone or ruxolitinib, BEZ, or combined daily for 10 days. The spleen weight along with the spleen images (E), and the donor leukemia percentage in the BM (F, left) and the spleen (F, right) are shown. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed Students’ t test. n = 4 mice per group.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts