Anti-PTK2 monoclonal antibody, clone 20I8

The potent DNA damaging agent bleomycin (BLM) is highly effective for treating various cancers, although, in certain individuals, the development of cellular resistance to the drug can severely diminish its antineoplastic properties. We performed two independent genome-wide screens using a Saccharomyces cerevisiae mutant collection to isolate variants exhibiting either sensitivity or resistance to BLM. This procedure reproducibly identified a relatively large collection of 231 BLM-hypersensitive mutants, representing genes belonging to diverse functional groups. In contrast, only five BLM-resistant mutants could be recovered by our screens. Among these latter mutants, three were deleted for genes involved in plasma membrane transport, including the L-carnitine transporter Agp2, as well as the kinases Ptk2 and Sky1, which are involved in regulating polyamine transport. We further showed that Agp2 acts as a transporter of BLM and that overexpression of this transporter significantly enhances BLM-induced cell killing. Our data strongly implicate membrane transport as a key determinant in BLM resistance in yeast. This finding is critical, given that very little is known about BLM transport in human cells. Indeed, characterization of analogous mechanisms in humans may ultimately lead to enhancement of the antitumor properties of BLM.

This study was to investigate the circular RNA (circRNA) expression profile and the potential circRNAs as biomarkers and therapeutic targets for acute myeloid leukaemia (AML). CircRNA expression profile in bone marrow mononuclear cells from 5 AML patients and 5 healthy donor controls (HCs) was evaluated by microarray. Then, 10 candidate circRNAs (top 5 upregulated and top 5 downregulated) from microarray were validated by RT-qPCR in 130 AML patients and 50 HCs. Finally, the effects of circRNA annexin A2 (circ-ANXA2) knockdown on cell proliferation, apoptosis, chemosensitivity to cytarabine, daunorbicin and potential target microRNAs were assessed in THP-1 and KG-1 cells. By microarray, 173 upregulated and 181 downregulated circRNAs were found in AML patients than HCs, and these circRNAs were found in AML patients compared with HCs, and these circRNAs were implicated in AML-related pathways such as ErbB and EGFR pathways. By RT-qPCR, 9 of 10 candidate circRNAs (including circ-RPS6KB1, circ-CSMD2, circ-PTK2, circ-ANXA2, circ-PWP2, circ-RBM5, circ-ZZEF1, circ-GSK3B and circ-FOXP1) were dysregulated in AML patients compared with HCs. Circ-ANXA2 correlated with higher disease risk, poor risk stratification, lower complete remission level, shorter event-free survival and overall survival in AML. In cellular experiments, circ-ANXA2 was upregulated in AML cell lines, and its knockdown suppressed proliferation, enhanced apoptosis of THP-1 and KG-1 cells and increased their chemosensitivity to cytarabine and daunorbicin. Additionally, circ-ANXA2 knockdown promoted microRNA (miR)-23a-5p and miR-503-3p expression in THP-1 and KG-1 cells. In conclusion, our findings provide a macroscopic view of the circRNA expression profile in AML, and demonstrate that circ-ANXA2 may be a potential biomarker and therapeutic target for AML.