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 3

p53–/–Lnk–/– pro-B progenitors initiate B-ALL, and Lnk–/–p53–/– B leukemic blasts resemble human Ph-like ALL.

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p53–/–Lnk–/– pro-B progenitors initiate B-ALL, and Lnk–/–p53–/– B leuke...
(A) LOH of the Lnk allele in p53–/–Lnk+/– mice. B-ALL blasts and normal myeloid, T cells, and mature B cells were purified by flow cytometric sorting (left panels), and subjected to PCR analysis of Lnk gene status (top right panel). Various HSPC populations from p53–/–Lnk+/– mice were purified and subjected to PCR analysis for Lnk gene status (bottom right panel). LSK, HSPCs (Lin–Sca1+Kit+); LKS-, myeloid progenitors (Lin–Sca1–Kit+); CLPs, (Lin–IL-7R+Flt3+KitloSca1lo). (B) Kaplan-Meier curves show the survival of mice transplanted with 1,000 LSK cells from 2-month-old Lnk–/–, p53–/–, or p53–/–Lnk–/– preleukemic mice. P value found using log-rank t test. n = 5 mice per group. (C) Kaplan-Meier curves show the survival of mice transplanted with 100,000 pro-B cells from young preleukemic p53–/–Lnk–/– mice. P value found using log-rank t test. n = 6 mice per group. (D) Enrichment plots of GSEA analysis using Lnk–/–p53–/– B leukemic blasts (4 samples) versus control B progenitors (11 samples consist of 3 WT, 3 Lnk–/–, 3 p53–/–, and 2 preleukemic p53–/–Lnk–/– mice) express data against Ph-like B-ALL gene signature from the previous publication (6). NES, normalized enrichment score; FDR, false discovery rate.