Abstract
B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer, with cure rates of ∼80%. MLL-rearranged (MLLr) B-ALL (MLLr-B-ALL) has, however, an unfavorable prognosis with common therapy refractoriness and early relapse, and therefore new therapeutic targets are needed for relapsed/refractory MLLr-B-ALL. MLLr leukemias are characterized by the specific expression of chondroitin sulfate proteoglycan-4, also known as neuron-glial antigen-2 (NG2). NG2 was recently shown involved in leukemia invasiveness and central nervous system infiltration in MLLr-B-ALL, and correlated with lower event-free survival (EFS). We here hypothesized that blocking NG2 may synergize with established induction therapy for B-ALL based on vincristine, glucocorticoids, and l-asparaginase (VxL). Using robust patient-derived xenograft (PDX) models, we found that NG2 is crucial for MLLr-B-ALL engraftment upon intravenous (i.v.) transplantation. In vivo blockade of NG2 using either chondroitinase-ABC or an anti-NG2-specific monoclonal antibody (MoAb) resulted in a significant mobilization of MLLr-B-ALL blasts from bone marrow (BM) to peripheral blood (PB) as demonstrated by cytometric and 3D confocal imaging analysis. When combined with either NG2 antagonist, VxL treatment achieved higher rates of complete remission, and consequently higher EFS and delayed time to relapse. Mechanistically, anti-NG2 MoAb induces neither antibody-dependent cell-mediated not complement-dependent cytotoxicity. NG2 blockade rather overrides BM stroma-mediated chemoprotection through PB mobilization of MLLr-B-ALL blasts, thus becoming more accessible to chemotherapy. We provide a proof of concept for NG2 as a therapeutic target for MLLr-B-ALL.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Bcell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer [1]
Using robust preclinical patient-derived xenograft (PDX) models, we show that neuron-glial antigen-2 (NG2) antagonists synergize with VxL-based induction therapy, leading to an extensive mobilization of MLLr-B cell acute lymphoblastic leukemia (B-ALL) blasts from bone marrow (BM) into peripheral blood (PB) where they become more accessible/sensitive to VxL-based chemotherapy, resulting in higher complete remission (CR) rates (CRRs), and higher eventfree survival (EFS) and delayed time to relapse
When equal numbers of NG2+ and NG2− B-ALL primary blasts (105 cells/ patient, n = 4) were intravenously (i.v.) infused into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice (NSG) mice, engraftment levels after 8 weeks were 3.5-fold higher in the PB of mice transplanted with NG2+ than in equivalent mice transplanted with NG2− blasts (11.2 ± 1.8% vs. 3.2 ± 1.5%, p = 0.008) (Fig. 1a, left and middle panels)
Summary
Despite the overall progress in treatment, relapsed BALL is the fifth most prevalent pediatric cancer, and B-ALL remains the most common cause of death from malignancy in children [6, 7]. Patients experiencing early relapse or therapy refractoriness have a poor long-term survival and, in these cases, the best therapeutic option is hematopoietic stem cell transplantation (HSCT) following induction into second remission. These patients commonly fail to achieve a second remission; current chemotherapy is associated with morbidity and serious side effects such as infertility, impaired development, and greater risk of secondary neoplasms [12, 13]. Innovative directed/ targeted therapeutic approaches are in high demand for high-risk B-ALL and relapsed/refractory (R/R) B-ALL, and targeting leukemia-initiating cells and CNS-infiltrating leukemia cells is key to overcome therapy resistance, relapse, and CNS disease [14, 15]
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