Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells

Abstract

The purposes of this study were to examine the biologic effects of the engagement of the interleukin-7 receptor (IL-7R) with recombinant human interleukin-7 (rhIL-7) in immunophenotypically distinct T-lineage acute lymphoblastic leukemia (ALL) blasts and to elucidate the biochemical nature of the IL-7R-linked transmembrane signal in rhIL-7-responsive T- lineage ALL blast populations. In the absence of costimulants, rhIL-7 stimulated the in vitro proliferation and colony formation of freshly isolated leukemic blasts from six to eight T-lineage ALL patients with a mean plating efficiency of 196 +/- 53 (background subtracted) colonies/10(5) blasts plated. Stimulation of T-lineage ALL blasts with rhIL-7 resulted in markedly enhanced tyrosine phosphorylation of six distinct phosphoproteins with molecular weights of 57, 72, 98, 123, 150, and 190 Kd, and induced a rapid increase in the production of inositol-1,4,5-trisphosphate (Ins-1,4,5-P3), which was inhibitable by the tyrosine-specific protein kinase inhibitor genistein, but not by the serine/threonine-specific protein kinase C inhibitor H7. Similarly, rhIL-7 stimulated Ins-1,4,5-P3 production in CEM-1.3 T-lineage ALL cells and this stimulation was inhibitable by the tyrosine-specific protein kinase inhibitors genistein and herbimycin A, but not by H-7. Thus, the transmembrane signal triggered by engagement of the IL-7R is intimately linked to a functional tyrosine-specific protein kinase pathway and stimulates the phosphoinositide (PI) turnover and proliferation of T-lineage ALL blasts. The presented data confirm and extend previous studies on the expression of functional IL-7R on T- lineage ALL blasts and support the hypothesis that IL-7 may play an important regulatory role in the biology of T-lineage ALL.

High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling

“…Most prior studies have focused on signaling via IL-7 (Dibirdik et al, 1991; Barata et al, 2004a,b,c, 2005; González-Garcia et al, 2009; Shochat et al, 2011; Silva et al, 2011) or mutational activation of intermediates in the PI3K–Akt pathway (Palomero et al, 2007; Gutierrez et al, 2009). The importance of PI3K–Akt activation in T-ALL is underscored by multiple studies showing that PI3K–Akt/mTOR inhibitors block growth/survival of T-ALL cells (Avellino et al, 2005; Wei et al, 2006; Palomero et al, 2007; Chiarini et al, 2009; Cullion et al, 2009).…”

“…Although previous works have focused on the role of IL-7 signaling in T-ALL, including effects on downstream PI3K–Akt activation (Dibirdik et al, 1991; Barata et al, 2004a,b,c, 2005; González-Garcia et al, 2009; Shochat et al, 2011; Silva et al, 2011), we considered that insulin-like growth factor (IGF)-1 receptor (IGF1R) may also play an important role. IGFs and their receptors regulate normal cell growth and contribute to transformation and growth of malignant cells in many contexts (Pollak et al, 2004).…”

Genes for interleukin 7 are transcribed in leukemic cell subsets of individuals with chronic lymphocytic leukemia.

“…CLL cells incubated with PE-streptavidin but without biotinylated IL-7 are indicated as the hatched lines over the solid peak. including CLL (42)(43)(44)(45). Most CLL cells, however, are not proliferating, but accumulating, as rather mature B cells.…”

CSL–MAML-dependent Notch1 signaling controls T lineage–specific IL-7Rα gene expression in early human thymopoiesis and leukemia

“…Similar to normal immature thymocytes, leukemic blasts from T cell acute lymphoblastic leukemia (T-ALL) patients can express functional IL-7Rs that support proliferation in response to IL-7 (37). Because gain-of-function mutations in Notch1 are common in T-ALL (38), we decided to investigate whether Notch signaling also controls IL-7R expression in T-ALLs.…”

“…Our observation that ectopic IL-7R could rescue the growth arrest induced by Notch deprivation not only in normal thymocytes but also in T-ALLs is, thus, remarkable. Importantly, IL-7R signaling significantly contributes to T-ALL proliferation by activation of PI3K (37), and constitutive PI3K activation has recently been shown to induce resistance to Notch1 inhibition in T-ALL (36). Therefore, downstream effectors of IL-7R, such as PI3K, represent suitable molecular targets for therapeutic intervention.…”