Leukemic IL‐17RB signaling regulates leukemic survival and chemoresistance

Abstract

Secreted proteins provide crucial signals that have been implicated in the development of acute myeloid leukemia (AML) in the bone marrow microenvironment. Here we identify aberrant expressions of inflammatory IL‐17B and its receptor (IL‐17RB) in human and mouse mixed lineage leukemia–rearranged AML cells, which were further increased after exposure to chemotherapy. Interestingly, silencing of IL‐17B or IL‐17RB led to significant suppression of leukemic cell survival and disease progression in vivo. Moreover, the IL‐17B–IL‐17RB axis protected leukemic cells from chemotherapeutic agent–induced apoptotic effects. Mechanistic studies revealed that IL‐17B promoted AML cell survival by enhancing ERK, NF‐κB phosphorylation, and the expression of antiapoptotic protein B‐cell lymphoma 2, which were reversed by small‐molecule inhibitors. Thus, the inhibition of the IL‐17B–IL‐17RB axis may be a valid strategy to enhance sensitivity and therapeutic benefit of AML chemotherapy.—Guo, H.‐Z., Niu, L.‐T., Qiang, W.‐T., Chen, J., Wang, J., Yang, H., Zhang, W., Zhu, J., Yu, S.‐H. Leukemic IL‐17RB signaling regulates leukemic survival and chemoresistance. FASEB J. 33, 9565–9576 (2019). http://www.fasebj.org

The Emerging Role of the IL-17B/IL-17RB Pathway in Cancer

“…Similar results were recently obtained in leukemic cells by Guo et al, who demonstrated that the IL-17RB pathway promotes the survival of MOLM-13 AML cells by increasing ERK and NF-KB phosphorylation and Bcl-2 level and consequently, resistance to the purine analog Ara-C, the frontline chemotherapeutic agent for AML (38). Importantly, in each study, inhibition of the IL-17B/IL-17RB axis by downregulating receptor expression in tumor cells or by using neutralizing anti-IL-17RB antibodies restored chemosensitivity in vitro (28,38) and in vivo (10). Similarly, IL-17B or IL-17RB silencing in cancer cells or treatment with antibodies targeting IL-17RB reduced proliferation of MDA-MB361 breast cancer cells and MOLM-13 AML cells in vitro and tumor growth in vivo in xenograft models based on these cell lines (28,38).…”

“…This leads to resistance to chemotherapeutic drugs, such as etoposide (a topoisomerase II inhibitor) (28), and paclitaxel (a spindle poison) (10). Similar results were recently obtained in leukemic cells by Guo et al, who demonstrated that the IL-17RB pathway promotes the survival of MOLM-13 AML cells by increasing ERK and NF-KB phosphorylation and Bcl-2 level and consequently, resistance to the purine analog Ara-C, the frontline chemotherapeutic agent for AML (38). Importantly, in each study, inhibition of the IL-17B/IL-17RB axis by downregulating receptor expression in tumor cells or by using neutralizing anti-IL-17RB antibodies restored chemosensitivity in vitro (28,38) and in vivo (10).…”

“…In line with the insilico analysis results, IL-17B, and IL-17RB mRNA and protein expression were significantly increased in AML blasts compared with cells from healthy controls. Particularly, their expression was dramatically increased in bone marrow supernatant from patients with AML compared with healthy donors (ELISA analysis) (38).…”

“…Importantly, in each study, inhibition of the IL-17B/IL-17RB axis by downregulating receptor expression in tumor cells or by using neutralizing anti-IL-17RB antibodies restored chemosensitivity in vitro (28,38) and in vivo (10). Similarly, IL-17B or IL-17RB silencing in cancer cells or treatment with antibodies targeting IL-17RB reduced proliferation of MDA-MB361 breast cancer cells and MOLM-13 AML cells in vitro and tumor growth in vivo in xenograft models based on these cell lines (28,38). Interestingly, IL-17RB knockdown in MOLM-13 AML cells had a stronger effect than IL-17B knockdown in vivo, reflecting the potential contribution of the microenvironment-derived IL-17B to the signal delivered to IL-17RB-positive leukemia cells.…”

Much More Than IL-17A: Cytokines of the IL-17 Family Between Microbiota and Cancer

“…In vivo, anti-IL-17RB monoclonal antibodies inhibited tumor metastasis and prolonged survival in a mouse xenograft model (171). Others confirmed a direct tumor-promoting activity of IL-17B in gastric cancer (172), thyroid cancer (173), and in acute myeloid leukemia (174).…”