Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 4, Pages 1267-1281Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI81468
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Funding
- NIH [R01 HL095675, R01 GM062820]
- Gabrielle's Angel Foundation for Cancer Research
- Alex's Lemonade for Childhood Cancer Research
- American Heart Association (AHA) postdoctoral fellowship
- Human Hematopoietic Stem Cell Center of Excellence [P30 DK090969]
- [T32HL007150]
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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/STATS 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.
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