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.
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Research Article Oncology

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

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

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Figure 4

LNK controls normal B cell and B-ALL development independently of Mpl pathway or its effects on HSCs.

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LNK controls normal B cell and B-ALL development independently of Mpl pa...
(A) Lnk–/–Mpl–/– double-null mice show decreased HSPC and myeloid progenitor compartments similar to Mpl–/– mice. LSK, Lin–Sca1+Kit+ cell fraction that contains both HSCs and multipotential progenitors; CMP, common myeloid progenitor, Lin–Sca1–Kit+CD34+FcrR–. **P < 0.01; ns, not significant, 2-tailed Student’s t test. n = 3–5 per group. (B) Lnk–/–Mpl–/– double-null mice show increased pre– and pro-B cell frequencies in the BM, similar to Lnk–/– mice. *P < 0.05; **P < 0.01; ns, not significant, 2-tailed Student’s t test. n = 3–4 per group. (C) p53–/–Lnk–/–Mpl–/– triple-null mice develop aggressive B-ALL similarly to p53–/–Lnk–/–double-null mice. The left panel shows flow analysis of BM B-ALL cells in p53–/–Lnk–/–Mpl–/– mice, and the right panel shows the Kaplan-Meier survival curves of p53–/–Lnk–/– and p53–/–Lnk–/–Mpl–/– mice. P value found using log-rank t test. n = 6–12 mice per group.