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Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML., Resistance to tyrosine kinase inhibitors (TKI) is a limitation to their use in treating chronic myelogenous leukemia (CML). Here, the authors show that targeting the ubiquitin peptidase USP47 overcomes TKI resistance and eliminates leukaemia stem/progenitor cells in primary and xenograft CML murine models.

Circular RNAs (circRNAs) are covalently closed RNA molecules in eukaryotes with features of high stability, tissue-specific and cell-specific expression. According to their biogenesis, circRNAs are mainly classified into five types, i.e. exonic circRNAs (EciRNAs), exon-intron circRNAs (EIciRNAs), intronic RNAs (CiRNAs), fusion circRNAs (f-circRNAs), and read-through circRNAs (rt-circRNAs). CircRNAs have been emerging as important non-coding regulatory RNAs in a variety of human cancers. CircRNA4s were revealed to exert regulatory function through multiple mechanisms, such as sponges/decoys of miRNAs and proteins, enhancers of protein functions, protein scaffolds, protein recruitment, or protein translation templates. Furthermore, some circRNAs are intensively associated with immune cells in tumor immune microenvironment (TIME), e.g. circARSP91 and natural killer cells. Through regulating immune checkpoint genes, circRNAs are demonstrated to modulate the immune checkpoint blockade immunotherapy, e.g. circCPA4 could up-regulate PD-L1 expression. In summary, we reviewed the molecular features of circRNAs and mechanisms how they exert functions. We further summarized functional implications of circRNA regulations in tumor immunology and immunotherapy. Further understanding of the regulatory roles of circRNAs in tumor immunology and immunotherapy will benefit tumor treatment.

Background and aims Pancreatic ductal adenocarcinoma (PDAC) is one of refractory malignancies without efficient therapeutics. Babao Dan (BBD) was partially effective to suppress tumor growth of PDAC in clinical practice. However, the molecular mechanisms were unclear. Methods We established PDAC mice models and treated them with BBD through intragastric administration. Treatment and control groups were then subjected to high-throughput RNA sequencing. We presented the transcriptional changes upon BBD treatment by using computational analysis comparing BBD treatment and control groups. Functional enrichment analysis was employed to investigate the biological processes or pathways that BBD modulates. Results BBD treatment showed strong suppression on tumor growth of PDAC, even stronger than Gemcitabine. Through differential analysis comparing BBD treatment and control groups, we identified 638 up-regulated and 259 down-regulated genes in the BBD treatment group. BBD was found to activate tumor suppressor genes, such as MTUS1, PDGFB, SOD3, and UCHL1. Furthermore, we revealed that BBD treatment inhibited cancer-related pathways and elevated activities of metabolism-related processes. The BBD-modulated metabolic genes were further showed to be associated with patient survival in an independent cohort with pancreatic cancer. Conclusion BBD repressed the tumor growth of PDAC. BBD treatment modulated expression of cancer-related genes in PDAC. BBD suppressed cancer-related pathways and activated metabolic processes in PDAC. Our study suggests BBD treatment as potential effective therapeutics for patients with pancreatic cancer.

The kinase FLT3 internal tandem duplication (FLT3-ITD) is related to poor clinical outcomes of acute myeloid leukemia (AML). FLT3 inhibitors have provided novel strategies for the treatment of FLT3-ITD-positive AML. But they are limited by rapid development of acquired resistance and refractory in monotherapy. Recent evidence shows that inducing the degradation of FLT3-mutated protein is an attractive strategy for the treatment of FLT3-ITD-positive AML, especially those with FLT3 inhibitor resistance. In this study we identified Wu-5 as a novel USP10 inhibitor inducing the degradation of FLT3-mutated protein. We showed that Wu-5 selectively inhibited the viability of FLT3 inhibitor-sensitive (MV4-11, Molm13) and -resistant (MV4-11R) FLT3-ITD-positive AML cells with IC(50) of 3.794, 5.056, and 8.386 μM, respectively. Wu-5 (1−10 μM) dose-dependently induced apoptosis of MV4-11, Molm13, and MV4-11R cells through the proteasome-mediated degradation of FLT3-ITD. We further demonstrated that Wu-5 directly interacted with and inactivated USP10, the deubiquitinase for FLT3-ITD in vitro (IC(50) value = 8.3 µM) and in FLT3-ITD-positive AML cells. Overexpression of USP10 abrogated Wu-5-induced FLT3-ITD degradation and cell death. Also, the combined treatment of Wu-5 and crenolanib produced synergistic cell death in FLT3-ITD-positive cells via the reduction of both FLT3 and AMPKα proteins. In support of this, AMPKα inhibitor compound C synergistically enhanced the anti-leukemia effect of crenolanib, while AMPKα activator metformin inhibited the anti-leukemia effect of crenolanib. In summary, we demonstrate that Wu-5, a novel USP10 inhibitor, can overcome FLT3 inhibitor resistance and synergistically enhance the anti-AML effect of crenolanib through targeting FLT3 and AMPKα pathway.