LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors
Ying Cheng, Kudakwashe Chikwava, Chao Wu, Haibing Zhang, Anchit Bhagat, Dehua Pei, John K. Choi, Wei Tong
Ying Cheng, Kudakwashe Chikwava, Chao Wu, Haibing Zhang, Anchit Bhagat, Dehua Pei, John K. Choi, Wei Tong
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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.