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Non-Hodgkin Lymphoma
Cyclin-dependent kinase 9 as a potential specific molecular target in NK-cell leukemia/lymphoma
Ferrata Storti Foundation
Shiori Kinoshita,1 Takashi Ishida,1,2 Asahi Ito,1 Tomoko Narita,1
Ayako Masaki,1,3 Susumu Suzuki,4 Takashi Yoshida,1 Masaki Ri,1
Shigeru Kusumoto,1 Hirokazu Komatsu,1 Norio Shimizu,5 Hiroshi Inagaki,3 Taruho Kuroda,6 Arne Scholz,7 Ryuzo Ueda,4 Takaomi Sanda8 and Shinsuke Iida1
1Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Japan; 2Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Japan; 3Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Japan; 4Department of Tumor Immunology, Aichi Medical University School of Medicine, Japan; 5Department of Virology, Division of Medical Science, Medical Research Institute, Tokyo Medical and Dental University, Japan; 6Bayer Yakuhin, Ltd., Osaka, Japan; 7Bayer AG Pharmaceuticals Division, Berlin, Germany; 8Cancer Science Institute of Singapore, National University of Singapore
Haematologica 2018 Volume 103(12):2059-2068
ABSTRACT
BAY 1143572 is a highly selective inhibitor of cyclin-dependent kinase 9/positive transcription elongation factor b. It has entered phase I clinical studies. Here, we have assessed the utility of BAY 1143572 for treating natural killer (NK) cell leukemias/lymphomas that have a poor prognosis, namely extranodal NK/T-cell lymphoma, nasal type and aggressive NK-cell leukemia, in a preclinical mouse model in vivo as well as in tissue culture models in vitro. Seven NK-cell leukemia/lymphoma lines and primary aggressive NK-cell leukemia cells from two individual patients were treated with BAY 1143572 in vitro. Primary tumor cells from an aggressive NK-cell leukemia patient were used to establish a xenogeneic murine model for testing BAY 1143572 therapy. Cyclin-dependent kinase 9 inhibition by BAY 1143572 resulted in prevention of phosphorylation at the serine 2 site of the C-terminal domain of RNA polymerase II. This resulted in lower c-Myc and Mcl-1 levels in the cell lines, causing growth inhibition and apoptosis. In aggressive NK-cell leukemia primary tumor cells, exposure to BAY 1143572 in vitro resulted in decreased Mcl-1 protein levels resulting from inhibition of RNA polymerase II C-terminal domain phosphorylation at the serine 2 site. Orally administering BAY 1143572 once per day to aggressive NK-cell leukemia-bearing mice resulted in lower tumor cell infiltration into the bone marrow, liver, and spleen, with less export to the periphery relative to control mice. The treated mice also had a sur- vival advantage over the untreated controls. The specific small molecule targeting agent BAY1143572 has potential for treating NK-cell leukemia/lymphoma.
Introduction
Extranodal natural killer (NK)/T-cell lymphoma (ENKTL), nasal type and aggres- sive NK-cell leukemia (ANKL), are both representative NK-cell leukemia/lym- phoma in which Epstein-Barr virus (EBV) is considered to play a critical role.1,2 ANKL is a systemic neoplastic proliferation of NK cells that has an aggressive clin- ical course, and a seriously poor prognosis, with a median survival of < 2 months.2- 5 There can be overlap with ENKTL, nasal type, showing systemic organ involve- ment; thus, it is unclear whether ANKL is the leukemic counterpart of ENKTL, nasal type.1,2 A regimen not containing anthracyclines, SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) has brought some
Correspondence:
itakashi@iwate-med.ac.jp
Received: February 15, 2018. Accepted: July 30, 2018. Pre-published: August 3, 2018.
doi:10.3324/haematol.2018.191395
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/12/2059
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