LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors.
In: Journal of Clinical Investigation, Jg. 126 (2016-04-01), Heft 4, S. 1267-1281
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Zugriff:
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. [ABSTRACT FROM AUTHOR]
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LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B-progenitors.
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Autor/in / Beteiligte Person: | Cheng, Ying ; Chikwava, Kudakwashe ; Wu, Chao ; Zhang, Haibing ; Bhagat, Anchit ; Pei, Dehua ; Choi, John K. ; Tong, Wei |
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Zeitschrift: | Journal of Clinical Investigation, Jg. 126 (2016-04-01), Heft 4, S. 1267-1281 |
Veröffentlichung: | 2016 |
Medientyp: | academicJournal |
ISSN: | 0021-9738 (print) |
DOI: | 10.1172/JCI81468 |
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