HIV INTEGRASE INHIBITOR MK-2048 INDUCES APOPTOSIS IN HTLV-1 INFECTED CELLS THROUGH THE UPR ACTIVATION.
Author(s): ,
Emi Ikebe
Affiliations:
Department of Safety Research on Blood and Biological Products,National Institute of Infectious Diseases,Tokyo,Japan
,
Sahoko Matsuoka
Affiliations:
Department of Safety Research on Blood and Biological Products,National Institute of Infectious Diseases,Tokyo,Japan
,
Kenta Tezuka
Affiliations:
Department of Safety Research on Blood and Biological Products,National Institute of Infectious Diseases,Tokyo,Japan
,
Madoka Kuramitsu
Affiliations:
Department of Safety Research on Blood and Biological Products,National Institute of Infectious Diseases,Tokyo,Japan
,
Kazu Okuma
Affiliations:
Department of Safety Research on Blood and Biological Products,National Institute of Infectious Diseases,Tokyo,Japan
,
Makoto Nakashima
Affiliations:
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences,The University of Tokyo,Tokyo,Japan
,
Seiichiro Kobayashi
Affiliations:
Division of Molecular Therapy, Institute of Medical Science,The University of Tokyo,Tokyo,Japan
,
Junya Makiyama
Affiliations:
Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science,The University of Tokyo,Tokyo,Japan
,
Makoto Yamagishi
Affiliations:
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences,The University of Tokyo,Tokyo,Japan
,
Seiichi Oyadomari
Affiliations:
Division of Molecular Biology, Institute for Genome Research,Tokushima University,Tokushima,Japan
,
Kaoru Uchimaru
Affiliations:
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences,The University of Tokyo,Tokyo,Japan;Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science,The University of Tokyo,Tokyo,Japan
Isao Hamaguchi
Affiliations:
Department of Safety Research on Blood and Biological Products,National Institute of Infectious Diseases,Tokyo,Japan
EHA Library. Ikebe E. Jun 15, 2019; 267233; PS932
Emi Ikebe
Emi Ikebe
Contributions
Abstract

Abstract: PS932

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

Human T-cell Leukemia virus type I (HTLV-1) is a retrovirus that infects peripheral T cells and causes several refractory diseases like HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL). Recently, Drug repositioning, the application of available drugs for treating conditions different from the original treatment purposes, has become a popular drug development strategy mainly because of the reduced development time and cost. A recent study demonstrated the strong cytotoxic effect of Abacavir, a nucleoside analog reverse transcriptase inhibitor for HIV-1, on ATL cells. Previous studies also reported that HIV integrase inhibitors (INIs) prevented HTLV-1 integration, but the effect of HIV IN inhibitors on HTLV-1-infected cell survival remains unclear.

Aims
To investigate the cytotoxic effect of MK-2048, a second-generation HIV-1 INI, on HTLV-1 infected cells.

Methods
HTLV-1 infected cell lines and ATL derived cell lines were treated with six different HIV INIs (BMS-707035, Raltegravir, Elvitegravir, Cabotegravir, Dolutegravir, and MK-2048) and the number of viable cells 0-4 days after the treatment was measured by a luminescence assay (Cell Titer). Subsequently, the effect of MK-2048 on HTLV-1 infected cells was evaluated by cell cycle (FACS) and apoptosis (Caspase-3/7 activity). Transcriptome profiling with microarrays, Quantitative PCR and Western blot (WB) analysis of HTLV-1 infected cell line and ATL cell line samples with and without MK-2048 treatment were performed. Finally, the effects of MK-2048 were confirmed in primary HTLV-1 carrier peripheral blood mononuclear cells (PBMCs).

Results
We found that MK-2048 has a particularly high growth inhibitory effect on HTLV-1 infected cells. Differential transcriptome profiling revealed significantly elevated gene expression of PKR-like ER kinase (PERK) signaling pathway of the unfolded protein response (UPR) in MK-2048-sensitive HTLV-1 infected cell lines and ATL cell lines after the treatment of MK-2048. Quantitative PCR and WB analysis showed that MK-2048 induces PERK-eIF2a-ATF4 pathway activation and elevates the expression of apoptosis markers including C/EBP homologous protein (CHOP) and cleaved Poly (ADP-ribose) polymerase  (PARP) in HTLV-1 infected cell lines. We also identified the significant downregulation of glucose regulatory protein 78 (GRP78), a master regulator of the UPR, in the CD4+CADM1+ HTLV-1-infected cell-enriched population of primary HTLV-1 carrier PBMCs (n = 9). MK-2048 efficiently reduced proviral loads in HTLV-1 carrier PBMCs (n = 4), but had no effect on the total numbers of HTLV-1 carrier PBMCs, indicating that MK-2048 does not affect the viability of HTLV-1-uninfected PBMCs. We also found that MK-2048 specifically induced CHOP in HTLV-1-infected cells of HTLV-1 carrier PBMCs by immunostaining.

Conclusion
Our findings demonstrated that MK-2048 selectively induces HTLV-1-infected cell death through the UPR activation. This novel regulatory mechanism of MK-2048 in HTLV-1-infected cells provides a promising prophylactic and therapeutic target for HTLV-1-related diseases including ATL.

Session topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research

Keyword(s): Apoptosis, Chemotherapy

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies