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.

Co-existence of IL7R high and SH2B3 low expression distinguishes a novel high-risk acute lymphoblastic leukemia with Ikaros dysfunction

“…We identified a subclass of high-risk ALL patients characterized as IL7R high SH2B3 low which is consistent with the reported effect of IL7R and SH2B3 in the oncogenesis of B-ALL [19, 21, 34]. It is reported that SH2B3 interacts with JAK3 and IL7R activates JAK3 in B cell lineages [20]. SH2B3 is a negative regulator for IL7R–mediated JAK/SAT signaling that contributes to precursor B-ALL development.…”

“…SH2B3 is a negative regulator for IL7R–mediated JAK/SAT signaling that contributes to precursor B-ALL development. Moreover, the elevated activations of STATs such as STAT5 are downstream of IL7R stimulation in ALL [20, 38]. STAT5 is considered indispensable for maintenance of BCR-ABL –positive leukemia [38].…”

“…Loss of function mutations in SH2B3 are reported to play an important role in oncogenesis of ALL [19, 20]. Loss of SH2B3 results in an increase in Janus kinase-signal transduction, activation of transcription signaling and lymphoid cell proliferation, which further promotes leukemia development in a mouse model of NOTCH1-induced ALL [20, 21].…”

“…SH2B3 regulates pro-B progenitor homeostasis by attenuating IL-7–stimulated JAK/STAT5 signaling via a direct interaction with phosphorylated JAK3. While SH2B3 suppresses IL-7R/JAK/STAT signaling to restrict pro-/pre-B progenitor expansion and leukemia development [20], Ikaros plays an essential role in lymphocyte development and functions as a tumor suppressor in leukemia. Ikaros dysfunction is associated with a high relapse rate and unfavorable outcome in high-risk ALL [24–26].…”

Targeting the phosphatidylinositol 3‐kinase/Akt/mechanistic target of rapamycin signaling pathway in B‐lineage acute lymphoblastic leukemia: An update

“…As to Ph‐like B‐ALL, aberrant PI3K/Akt/mTOR signaling has been reported in this disease subset which frequently displays a wide array of genetic anomalies which result in upregulation of signaling pathways downstream of LNK/SH2B3, CLRF2, JAK 1/2, IL‐7Rα, Abl 1/2, platelet‐derived growth factor receptor‐β (PDGFRB), colony‐stimulating factor‐1 receptor (CSF1R), and erythropoietin receptor (EPOR) (Cheng et al, ; Reshmi et al, ). All of these aberrations have the potential for driving PI3K/Akt/mTOR signaling (Maude et al, ; Tasian et al, ; Vo et al, ) (Figure c).…”