Abstract

T-cell acute lymphoblastic leukemia (T-ALL), a malignant neoplasm of immature T cells, is particularly aggressive leukemia with no targeted therapies. Large-scale sequencing efforts to define the genetic make-up of tumors both at diagnosis and during relapse have provided little actionable information for therapeutic development or predict relapse. T-ALL is reliant on the growth factors and chemokines from the bone marrow (BM) microenvironment for its growth, survival, and BM retention. To identify possible vulnerabilities, we have previously examined the role of CXCL12, a chemokine produced by the BM niche, in maintaining NOTCH1 (Notch1-DE) mutation-driven T-ALL 1. Targeting CXCL12/CXCR4 signaling after leukemic onset reduced the T-ALL burden in murine disease models, suggesting that the CXCL12-CXCR4 could be a viable therapeutic target in human T-ALL.To test the therapeutic role of CXCR4 in human T-ALL, we generated CXCR4 knockout T-ALL cell lines using CRISPR-Cas9 editing and characterized their growth and survival in vitro and in vivo. Although the effect of CXCR4 targeting on leukemic growth and apoptosis in vitro was modest (Figure 1A-B), animals engrafted with CXCR4 knockout T-ALL cell lines survived significantly longer than mice injected with control leukemic cells (Figure 1C). To investigate the clinical efficacy of targeting the CXCR4/CXCL12 axis in primary human T-ALL, we generated T-ALL patient-derived xenografts (PDXs) mouse models from 5 T-ALL and 2 Early T-cell precursor acute ALL (ETP-ALL) primary samples. Remarkably, treating PDX mice with MDX1338, a fully humanized anti-CXCR4 antibody2,3, significantly extended survival from all tested PDX models independently of their mutational landscape (Figure 1D-E). This increased survival was accompanied by mobilization of leukemic cells into peripheral blood, suggesting that CXCR4 targeting leads to leukemic disengagement from the BM niche, affecting their survival. Furthermore, BM imaging revealed disengagement of leukemic cells from the BM niche. Collectively, this study provides a pre-clinical rationale for therapeutic interventions targeting CXCR4 in human T-ALL. Figure 1: CXCR4 antagonism suppresses human T-ALL in vivo. A-B) Growth curve (A) and level of Annexin V (B) of human T-ALL cell lines CRISPR/Cas9-edited with sgCXCR4 or control sgOR2W5. C) Kaplan-Meier survival curves of recipient mice transduced with sgOR2W5 or two independent sgCXCR4 are plotted. D) Schematic of treatment with aCXCR4 Ab (MDX-1338) or isotype control. E-F) Kaplan-Meier survival graph (left) and peripheral blood levels of hCD45+ of NSG mice engrafted with primary adult (E) and pediatric (F) T-ALL samples and treated with aCXCR4 Ab or isotype control. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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