Blocking UBE2N abrogates oncogenic immune signaling in acute myeloid leukemia.
Sci Transl Med
california; santa monica; sjci; sjhc; genomics; Cell Proliferation; Humans; Leukemia, Myeloid, Acute; Oncogenes; Signal Transduction; Ubiquitin-Conjugating Enzymes
Dysregulation of innate immune signaling pathways is implicated in various hematologic malignancies. However, these pathways have not been systematically examined in acute myeloid leukemia (AML). We report that AML hematopoietic stem and progenitor cells (HSPCs) exhibit a high frequency of dysregulated innate immune-related and inflammatory pathways, referred to as oncogenic immune signaling states. Through gene expression analyses and functional studies in human AML cell lines and patient-derived samples, we found that the ubiquitin-conjugating enzyme UBE2N is required for leukemic cell function in vitro and in vivo by maintaining oncogenic immune signaling states. It is known that the enzyme function of UBE2N can be inhibited by interfering with thioester formation between ubiquitin and the active site. We performed in silico structure-based and cellular-based screens and identified two related small-molecule inhibitors UC-764864/65 that targeted UBE2N at its active site. Using these small-molecule inhibitors as chemical probes, we further revealed the therapeutic efficacy of interfering with UBE2N function. This resulted in the blocking of ubiquitination of innate immune- and inflammatory-related substrates in human AML cell lines. Inhibition of UBE2N function disrupted oncogenic immune signaling by promoting cell death of leukemic HSPCs while sparing normal HSPCs in vitro. Moreover, baseline oncogenic immune signaling states in leukemic cells derived from discrete subsets of patients with AML exhibited a selective dependency on UBE2N function in vitro and in vivo. Our study reveals that interfering with UBE2N abrogates leukemic HSPC function and underscores the dependency of AML cells on UBE2N-dependent oncogenic immune signaling states.
Barreyro, Laura; Sampson, Avery M; Ishikawa, Chiharu; Hueneman, Kathleen M; Choi, Kwangmin; Pujato, Mario A; Chutipongtanate, Somchai; Wyder, Michael; Haffey, Wendy D; O'Brien, Eric; Wunderlich, Mark; Ramesh, Vighnesh; Kolb, Ellen M; Meydan, Cem; Neelamraju, Yaseswini; Bolanos, Lyndsey C; Christie, Susanne; Smith, Molly A; Niederkorn, Madeline; Muto, Tomoya; Kesari, Santosh; Garrett-Bakelman, Francine E; Bartholdy, Boris; Will, Britta; Weirauch, Matthew T; Mulloy, James C; Gul, Zartash; Medlin, Stephen; Kovall, Rhett A; Melnick, Ari M; Perentesis, John P; Greis, Kenneth D; Nurmemmedov, Elmar; Seibel, William L; and Starczynowski, Daniel T, "Blocking UBE2N abrogates oncogenic immune signaling in acute myeloid leukemia." (2022). Articles, Abstracts, and Reports. 5881.