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 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.