title: 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.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.forename: Kudakwashe
authors.initials: K
authors.lastname: Chikwava
authors.forename: Chao
authors.initials: C
authors.lastname: Wu
authors.forename: Haibing
authors.initials: H
authors.lastname: Zhang
authors.forename: Anchit
authors.initials: A
authors.lastname: Bhagat
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010677:Philadelphia Chromosome; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D053616:Janus Kinase 3; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C490777:Lnk protein, mouse; C490778:SH2B3 protein, human; C495901:TP53 protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse