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.

• Authors: He-Zhou Guo, Li-Ting Niu, Wan-Ting Qiang, Juan Chen, Juan Wang, Hui Yang, Wu Zhang, Jiang Zhu, Shan-He Yu
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 8 Pg. 9565-9576 (08 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 31136196 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Interleukin-17
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Interleukin-17

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Computational Biology
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Immunohistochemistry
• Interleukin-17 (therapeutic use)
• Leukemia, Myeloid, Acute (drug therapy, metabolism)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptors, Interleukin-17 (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)