Annual Report 2018

Division of Molecular Oncology

Keisuke Kataoka, Junji Koya, Yasunori Kogure, Sumito Shingaki, Yuki Saito, Mariko Tabata, Yuji Kumade, Shizue Ichimura, Miki Sagou, Fumie Ueki, Yoko Hokama

Introduction

 The advent of next-generation sequencing (NGS) technologies has allowed us to delineate the genetic landscape of human cancers and we have leveraged NGS to work on the integrated genetic analysis of various cancers, especially hematologic malignancies. By combining genomics with molecular and functional approaches, we aim to:

1) Genetically dissect the molecular pathogenesis of human cancers.

2) Identify novel potential therapeutic targets and/or biomarkers.

3)  Establish the clinical relevance of genetic alterations.

The Team and What We Do

 Using the above-mentioned approaches, in recent years, we have revealed the genetic portrait of adult T-cell leukemia/lymphoma (ATL) (K Kataoka et al., Nat Genet. 2015). In addition, performing pan-cancer analysis based on this study allowed us to identify PD-L1 genetic alterations leading to cancer immune evasion in wide-ranging cancers (K Kataoka et al., Nature. 2016).

Research activities

 Recently, we investigated PD-L1/PD-L2 genetic alterations (structural variations and copy number alterations) in various subtypes of B-cell and T-cell lymphomas and found that these lesions are frequently observed in primary mediastinal B-cell lymphoma and mature NK/ T-cell neoplasms, such as extranodal NK/T-cell lymphoma, nasal type. In addition, PD-L1/PDL2 genetic alterations are strongly associated with Epstein-Barr virus infection (K Kataoka et al., Leukemia). We also performed an integrated genetic analysis in more than 130 patients with peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) and delineated their entire landscape of genetic alterations. Through these analyses, we found a number of new genetic targets and identified a novel subtype characterized by TP53 and CDKN2A alterations and extensive genomic instability. Our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help devise a novel molecular classification of PTCLs and exploit a new therapeutic strategy for this group of aggressive malignancies (Y Watatani et al., Leukemia).

Future prospects

 As shown in the ATL project, we aim to delineate the entire picture of genetic aberrations in human cancers using NGS. Based on the genetic findings, we will identify novel potential drug targets and/or biomarkers and clarify the molecular pathogenesis underlying how cancers develop and progress. We will also establish the clinical significance of these alterations, which can help cancer precision medicine.

List of papers published in 2018

Journal

 1. Chung EY, Mai Y, Shah UA, Wei Y, Ishida E, Kataoka K, Ren X, Pradhan K, Bartholdy B, Wei X, Zou Y, Zhang J, Ogawa S, Steidl U, Zang X, Verma A, Janakiram M, Ye BH. PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma. Clin Cancer Res, 2019

 2. Kataoka K, Miyoshi H, Sakata S, Dobashi A, Couronne L, Kogure Y, Sato Y, Nishida K, Gion Y, Shiraishi Y, Tanaka H, Chiba K, Watatani Y, Kakiuchi N, Shiozawa Y, Yoshizato T, Yoshida K, Makishima H, Sanada M, Onozawa M, Teshima T, Yoshiki Y, Ishida T, Suzuki K, Shimada K, Tomita A, Kato M, Ota Y, Izutsu K, Demachi-Okamura A, Akatsuka Y, Miyano S, Yoshino T, Gaulard P, Hermine O, Takeuchi K, Ohshima K, Ogawa S. Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. Leukemia, 2019

 3. Becker H, Greve G, Kataoka K, Mallm JP, Duque-Afonso J, Ma T, Niemoller C, Pantic M, Duyster J, Cleary ML, Schuler J, Rippe K, Ogawa S, Lubbert M. Identification of enhancer of mRNA decapping 4 as a novel fusion partner of MLL in acute myeloid leukemia. Blood Adv, 3:761-765, 2019

 4. Yokoyama A, Kakiuchi N, Yoshizato T, Nannya Y, Suzuki H, Takeuchi Y, Shiozawa Y, Sato Y, Aoki K, Kim SK, Fujii Y, Yoshida K, Kataoka K, Nakagawa MM, Inoue Y, Hirano T, Shiraishi Y, Chiba K, Tanaka H, Sanada M, Nishikawa Y, Amanuma Y, Ohashi S, Aoyama I, Horimatsu T, Miyamoto S, Tsunoda S, Sakai Y, Narahara M, Brown JB, Sato Y, Sawada G, Mimori K, Minamiguchi S, Haga H, Seno H, Miyano S, Makishima H, Muto M, Ogawa S. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature, 565:312-317, 2019

 5. Subramanian K, Dierckx T, Khouri R, Menezes SM, Kagdi H, Taylor GP, Farre L, Bittencourt A, Kataoka K, Ogawa S, Van Weyenbergh J. Decreased RORC expression and downstream signaling in HTLV-1-associated adult T-cell lymphoma/leukemia uncovers an antiproliferative IL17 link: A potential target for immunotherapy? Int J Cancer, 144:1664-1675, 2019

 6. Kotani S, Yoda A, Kon A, Kataoka K, Ochi Y, Shiozawa Y, Hirsch C, Takeda J, Ueno H, Yoshizato T, Yoshida K, Nakagawa MM, Nannya Y, Kakiuchi N, Yamauchi T, Aoki K, Shiraishi Y, Miyano S, Maeda T, Maciejewski JP, Takaori-Kondo A, Ogawa S, Makishima H. Molecular pathogenesis of disease progression in MLL-rearranged AML. Leukemia, 33:612-624, 2019

 7. Koya J, Kataoka K. More accurate prognostic prediction in diffuse large B-cell lymphoma: beyond cell-of-origin. Ann Oncol, 29:2284-2286, 2018

 8. Taoka K, Arai S, Kataoka K, Hosoi M, Miyauchi M, Yamazaki S, Honda A, Aixinjueluo W, Kobayashi T, Kumano K, Yoshimi A, Otsu M, Niwa A, Nakahata T, Nakauchi H, Kurokawa M. Using patient-derived iPSCs to develop humanized mouse models for chronic myelomonocytic leukemia and therapeutic drug identification, including liposomal clodronate. Sci Rep, 8:15855, 2018

 9. Kataoka K, Ogawa S. PD-1 Inhibitor Therapy in Adult T-Cell Leukemia-Lymphoma. N Engl J Med, 379:696, 2018

10. Shiozawa Y, Malcovati L, Galli A, Sato-Otsubo A, Kataoka K, Sato Y, Watatani Y, Suzuki H, Yoshizato T, Yoshida K, Sanada M, Makishima H, Shiraishi Y, Chiba K, Hellstrom-Lindberg E, Miyano S, Ogawa S, Cazzola M. Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia. Nat Commun, 9:3649, 2018

11. Shah UA, Chung EY, Giricz O, Pradhan K, Kataoka K, Gordon-Mitchell S, Bhagat TD, Mai Y, Wei Y, Ishida E, Choudhary GS, Joseph A, Rice R, Gitego N, Parrish C, Bartenstein M, Goel S, Mantzaris I, Shastri A, Derman O, Binder A, Gritsman K, Kornblum N, Braunschweig I, Bhagat C, Hall J, Graber A, Ratner L, Wang Y, Ogawa S, Verma A, Ye BH, Janakiram M. North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies. Blood, 132:1507-1518, 2018

12. Toki T, Yoshida K, Wang R, Nakamura S, Maekawa T, Goi K, Katoh MC, Mizuno S, Sugiyama F, Kanezaki R, Uechi T, Nakajima Y, Sato Y, Okuno Y, Sato-Otsubo A, Shiozawa Y, Kataoka K, Shiraishi Y, Sanada M, Chiba K, Tanaka H, Terui K, Sato T, Kamio T, Sakaguchi H, Ohga S, Kuramitsu M, Hamaguchi I, Ohara A, Kanno H, Miyano S, Kojima S, Ishiguro A, Sugita K, Kenmochi N, Takahashi S, Eto K, Ogawa S, Ito E. De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome. Am J Hum Genet, 103:440-447, 2018

13. Shiraishi Y, Kataoka K, Chiba K, Okada A, Kogure Y, Tanaka H, Ogawa S, Miyano S. A comprehensive characterization of cis-acting splicing-associated variants in human cancer. Genome Res, 28:1111-1125, 2018