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 6

p53–/–Lnk–/– progenitor cells show increased self-renewal and superior responses to IL-7 in vitro and in vivo.

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p53–/–Lnk–/– progenitor cells show increased self-renewal and superior ...
(A) The serial replating abilities of purified pro-B cells from mice of 4 different genotypes in the presence of IL-7 and SCF are shown. Representative graph of 5 independent experiments is shown. (B) The colony formation ability of p53–/– or p53–/–Lnk–/– pro-B cells at the 4th replating in different concentrations of IL-7 along with 20 ng/ml SCF are shown. Representative graph of 4 independent experiments is shown. (C) Photomicrograph of colonies plated in methylcellulose in different cytokine conditions (×40). (D) Log growth of purified pro-B cells cultured on OP-9 stromal cells supplemented with IL-7/SCF/Flt3L. Representatives of 4 independent experiments are shown. (E) p53–/–Lnk–/– progenitor cells show increased ability to generate B cells in vivo. pro-B cells (1 × 105)were purified from 2-month-old WT, Lnk–/–, p53–/–, or p53–/–Lnk–/– mice; mixed with 3 × 105 competitor BM cells; and transplanted into lethally irradiated recipients. Chimerisms of donor-derived IgM+IgD+ mature and IgM–IgD+ immature B cells in the spleen of the transplanted mice are shown. n = 4–6 mice per group. Representative results from 2 independent experiments are shown. **P < 0.01; ***P < 0.001, 2-tailed Students’ t test.