IL-7R is essential for leukemia-initiating cell activity of T-cell acute lymphoblastic leukemia

Abstract

Key Points IL-7R expression is a functional biomarker of T-ALL cells with leukemia-initiating potential and plays a crucial role in T-ALL pathogenesis. Targeting IL-7R–mediated signaling hampers leukemia-initiating activity and progression of human T-ALL.

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

“…Here, we evaluated the impact of CIGB-300 on T-ALL cell viability and proliferation. Taking into consideration the role of IL-7 in promoting T-ALL cell survival and proliferation in vitro [ 39 , 40 , 41 , 42 , 43 ] and T-ALL expansion in vivo [ 44 , 45 ], we also determined the ability of CIGB-300 to target leukemia cells in the presence of IL-7. Furthermore, since other extrinsic signals can contribute to T-ALL cell survival, we evaluated whether murine OP9-delta-like 1 (DL1) stromal cells counteracted the cytotoxic effect of CIGB-300 in co-culture experiments.…”

Facts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia

“…IL-7 also plays a relevant role in the maintenance and survival of naïve [ 222 , 223 ] and memory peripheral T cells [ 224 , 225 , 226 , 227 , 228 ], as well as in innate lymphoid cell development [ 229 , 230 ]. Given that T-ALL arises from the malignant transformation of immature T-cell progenitors, it was not unforeseen that a high proportion (more than 70%) of T-ALL cases express functional IL-7Rs that mediate proliferative and prosurvival signals in response to IL-7 [ 231 , 232 , 233 , 234 ]. More recently, a possible role of IL-7R in T-ALL molecular pathogenesis started to become apparent after discovering that IL-7R is a direct target of NOTCH1 and is involved in Notch-mediated T-ALL cell maintenance [ 235 ].…”

“…NOTCH1 signaling induces IL-7R expression by transcriptional upregulation of the IL7R gene (encoding IL-7R) through binding of the CSL/MAML-1 transcriptional complex to the IL7R promoter [ 235 ], a mechanism conserved in the mouse [ 234 ]. In addition, genome-wide mapping of NOTCH1 DNA-binding sites has highlighted a major role of super-enhancers in the dynamic regulation of NOTCH1 target genes including IL7R [ 236 ].…”

“…More importantly, up to 10% of T-ALL cases harbor activating mutations in genes encoding different molecular effectors downstream of IL-7R signaling, including JAK1, JAK3 and STAT5B (reviewed in [ 199 ]), reinforcing the role of IL-7R in leukemia cell proliferation. Recently, direct proof has been provided that IL-7R signaling does, in fact, contribute to T-ALL pathogenesis [ 234 ]. Using loss-of-function approaches, it was formally established that IL-7R signaling is essential for Notch1 oncogenicity and T-cell leukemogenesis.…”

“…Using loss-of-function approaches, it was formally established that IL-7R signaling is essential for Notch1 oncogenicity and T-cell leukemogenesis. The work also demonstrated that IL-7R expression contributes to human T-ALL LIC function, and revealed that IL-7R is a functional biomarker of T-ALL cells with LIC potential, a finding that was extended to B-ALLs expressing IL-7R [ 234 ]. The realization that IL-7R/IL-7 signaling directly contributes to T-ALL LIC activity has important clinical implications, as new therapeutic developments against leukemia mostly rely on molecular targets of LIC cells, which are finally responsible of disease relapse [ 51 , 245 ].…”