Abstract
As previously reported, chronic lymphocytic leukemia (CLL) cells show constitutive Notch1/2 activation and express the Notchligand Jagged1. Despite increasing knowledge of the impact of Notch alterations on CLL biology and pathogenesis, the role of Jagged1 expressed in CLL cells remains undefined. In other cell types, it has been shown that after Notch engagement, Jagged1 not only activates Notch in signal-receiving cell, but also undergoes proteolytic activation in signal-sending cell, triggering a signaling with biological effects. We investigated whether Jagged1 expressed in CLL cells undergoes proteolytic processing and/or is able to induce Notch activation through autocrine/paracrine loops, focusing on the effect that CLL prosurvival factor IL-4 could exert on the Notch-Jagged1 system in these cells. We found that Jagged1 was constitutively processed in CLL cells and generated an intracellular fragment that translocated into the nucleus, and an extracellular fragment released into the culture supernatant. IL-4 enhanced expression of Jagged1 and its intracellular fragments, as well as Notch1/2 activation. The IL-4-induced increase in Notch1/2 activation was independent of the concomitant upregulated Jagged1 levels. Indeed, blocking Notch-Jagged1 interactions among CLL cells with Jagged1 neutralizing antibodies did not affect the expression of the Notch target Hes1. Notably, anti-Jagged1 antibodies partially prevented the IL-4-induced increase in Jagged1 processing and cell viability, suggesting that Jagged1 processing is one of the events contributing to IL-4-induced CLL cell survival. Consistent with this, Jagged1 silencing by small interfering RNA partially counteracted the capacity of IL-4 to promote CLL cell survival. Investigating the pathways whereby IL-4 promoted Notch1/2 activation in CLL cells independent of Jagged1, we found that PI3Kδ/AKT and PKCδ were involved in upregulating Notch1 and Notch2 proteins, respectively. Overall, this study provides new insights into the Notch-ligand system in CLL cells and suggests that targeting this system may be exploited as a novel/additional therapy approach for CLL.
Highlights
The Notch receptor-ligand system mediates cell–cell communications and coordinates cell fate decisions in many contexts[1,2]
Investigating the pathways whereby IL-4 promoted Notch1/2 activation in chronic lymphocytic leukemia (CLL) cells independent of Jagged[1], we found that PI3Kδ/AKT and PKCδ were involved in upregulating Notch[1] and Notch[2] proteins, respectively
IL-4 is provided by different T-cell subsets in a lymph node microenvironment where CLL cells show hyperactivated Notch[134,43]. Based on all these observations, we investigated whether Jagged[1] expressed in CLL cells undergoes proteolytic processing and/or is able to induce Notch activation through autocrine/paracrine loops, focusing on the effect that IL-4 may exert on the Notch-Jagged[1] system in these cells
Summary
The Notch receptor-ligand system mediates cell–cell communications and coordinates cell fate decisions in many contexts[1,2]. Notch signaling initiates in the signalreceiving cells when Notch receptors (Notch1–4) bind their ligands, from Jagged (Jag) or Delta-like (Dll) families, expressed on the signal-sending cells. Following Notch engagement, some Notch ligands activate Notch signaling in signalreceiving cells, and undergo intramembrane proteolysis in signal-sending cells[4,5] This process induces the release of an intracellular domain of the ligand which, like. Notch-IC, acts as a signaling molecule, entering the nucleus and inducing transcriptional activation with consequent cellular responses[6,7,8,9,10] In this context, there is evidence that Jag[1] intracellular domain (Jag1-IC) increases AP-1 transcription factor activity[6], that drives the expression of several cancer-related genes. Jag1-IC controls mRNA expression of Jag[1] itself and Notch[3], playing a key role in cellular transformation[10] and neoplastic cell proliferation[11], and representing a link between aberrant Jag[1] expression and tumorigenesis
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