Molecular pathogenesis of bone marrow failure elucidated by comprehensive sequencing.

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16H05338
• Research Institution: Kyoto University
• Principal Investigator: 牧島 秀樹 京都大学, 医学研究科, 准教授 (40402127)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 骨髄不全症候群 / 再生不良性貧血 / 発作性夜間血色素尿症 / 骨髄異形成症候群 / 遺伝子変異 / コピー数異常 / 遺伝子発現異常 / 二次性白血病

Outline of Annual Research Achievements

本研究では、骨髄不全症候群において、ゲノムおよびトランスクリプトームの異常を併せて解析することにより、骨髄不全症・二次性の白血病化の病因および病態を明らかにすることを計画した。当初の予定通り、ゲノムシーケンスおよびRNAシーケンスを同一症例において行い、新規ゲノム異常および異常スプライシング・異常遺伝子発現を検索した。同時に、これらの解析を経時的検体を用いて行い、骨髄不全症におけるクローン構造を検討した。まず、ゲノムシーケンスにより、遺伝変異と染色体のコピー数を統合的に解析することにより、クロマチン再構築に関わるSWI/SNF複合体に含まれるARID2遺伝子に機能喪失型の変異および、機能低下をともなう欠失病変を発見した。これらの異常についてクローン構造の検討を行い、骨髄不全症の初期病変として獲得されることを世界で初めて明らかにした。さらには、ゲノムシーケンスとRNAシーケンスを同時に解析することにより、遺伝子発現に関連した骨髄異形成症候群の病型が、新規の幹細胞フェノタイプと赤芽球系フェノタイプへ分類されることを提唱し、遺伝子変異陽性クローン拡大に起因する高頻度の白血病化の原因を解明した。最も著明な成果は、再生不良性貧血後のクローン拡大に関するゲノム異常の検討である。これまでの最大症例数において経時的検体を用いて、７番染色体欠失および新規SETBP1・RUNX1変異の関与を明らかにした。これらの異常は、白血病へ進行しない症例にはほとんど認められなかった。それに加えて、先天性骨髄不全症候群を有する多臓器疾患において、新規SAMD9/SAMD9L胚細胞変異と、その対側正常アリルの欠失異常を同時に検出した。以上のゲノム異常のうち、重要な発見に関しては、マウスモデルを用いた機能解析を行うと同時に、予後・治療反応性等の臨床情報をも併せて解析し、臨床経過と関連する遺伝学的異常を検出した。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Cleveland Clinic./Case Western Reserve University.(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Cleveland Clinic./Case Western Reserve University.
• [Int'l Joint Research] Munich Leukemia Laboratory./University of Freiburg.(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Munich Leukemia Laboratory./University of Freiburg.
• [Int'l Joint Research] University of Pavia.(イタリア)
  • Country Name: ITALY
  • Counterpart Institution: University of Pavia.
• [Int'l Joint Research] University of Amsterdam.(オランダ)
  • Country Name: NETHERLANDS
  • Counterpart Institution: University of Amsterdam.
• [Int'l Joint Research] King Chulalongkorn Memorial Hospital.(タイ)
  • Country Name: THAILAND
  • Counterpart Institution: King Chulalongkorn Memorial Hospital.
• [Int'l Joint Research]
  • # of Other Countries: 2
• [Journal Article] Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma. (2019)
  • Author(s): Polprasert C, Takeuchi Y, Kakiuchi N, Yoshida K, Assanasen T, Sitthi W, Bunworasate U, Pirunsarn A, Wudhikarn K, Lawasut P, Uaprasert N, Kongkiatkamon S, Moonla C, Sanada M, Akita N, Takeda J, Fujii Y, Suzuki H, Nannya Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Rojnuckarin P, Ogawa S, Makishima H.
  • Journal Title: Blood Adv. Volume: 3 Pages: 588-595
  • DOI: 10.1182/bloodadvances.2018028340.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. (2019)
  • Author(s): Kataoka K, Miyoshi H, Sakata S, Dobashi A, Couronn 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, et al., Ogawa S.
  • Journal Title: Leukemia. Volume: - Pages: -
  • DOI: 10.1038/s41375-019-0380-5.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Age-related remodelling of oesophageal epithelia by mutated cancer drivers. (2019)
  • Author(s): Yokoyama A, Kakiuchi N, Yoshizato T, Nannya Y, et al, Makishima H, Muto M, Ogawa S.
  • Journal Title: Nature. Volume: 565 Pages: 312-317
  • DOI: 10.1038/s41586-018-0811-x.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular pathogenesis of disease progression in MLL-rearranged AML. (2019)
  • Author(s): 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.
  • Journal Title: Leukemia. Volume: 33 Pages: 612-624
  • DOI: 10.1038/s41375-018-0253-3.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clonal hematopoiesis in aplastic anemia. (2018)
  • Author(s): Makishima H.
  • Journal Title: Rinsho Ketsueki. Volume: 59 Pages: 1962-1968
  • DOI: 10.11406/rinketsu.59.1962.
  • Peer Reviewed
• [Journal Article] Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes. (2018)
  • Author(s): Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, Shima H, Aly M, Pastor V, Kuzmanovic T, Radivoyevitch T, Adema V, Awada H, Yoshida K, Li S, Sole F, Hanna R, Jha BK, LaFramboise T, Ogawa S, Sekeres MA, Wlodarski MW, Cammenga J, Maciejewski JP.
  • Journal Title: Blood. Volume: 132 Pages: 2309-2313
  • DOI: 10.1182/blood-2017-05-787390.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia. (2018)
  • Author(s): Shiozawa Y, Malcovati L, Gall 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.
  • Journal Title: Nat Commun. Volume: 9 Pages: 3649
  • DOI: 10.1038/s41467-018-06063-x.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clonal PIGA mosaicism and dynamics in paroxysmal nocturnal hemoglobinuria. (2018)
  • Author(s): Clemente MJ, Przychodzen B, Hirsch CM, Nagata Y, Bat T, Wlodarski MW, Radivoyevitch T, Makishima H, Maciejewski JP.
  • Journal Title: Leukemia. Volume: 32 Pages: 2507-2511
  • DOI: 10.1038/s41375-018-0138-5.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IDH1/2 Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1/2-Mutant Inhibitors. (2018)
  • Author(s): Molenaar RJ, Radivoyevitch T, Nagata Y, Khurshed M, Przychodzen B, Makishima H, Xu M, Bleeker FE, Wilmink JW, Carraway HE, Mukherjee S, Sekeres MA, van Noorden CJF, Maciejewski JP.
  • Journal Title: Clin Cancer Res. Volume: 24 Pages: 1705-1715.
  • DOI: 10.1158/1078-0432.CCR-17-2796.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 再生不良性貧血とクローン性造血 (2018)
  • Author(s): 牧島秀樹
  • Organizer: 日本血液学会総会
  • Invited
• [Presentation] Somatic and Germline Mutations in Myelodysplastic Syndromes. (2018)
  • Author(s): Hideki Makishima
  • Organizer: The 6th TSH International Symposium.
  • Int'l Joint Research / Invited
• [Presentation] Sequential acquisition of mutations in myelodysplastic syndromes. (2018)
  • Author(s): Hideki Makishima
  • Organizer: 41st IRCMS Seminar.
  • Int'l Joint Research / Invited
• [Presentation] Sequential acquisition of genetic mutations in myelodysplastic syndromes (MDS). (2018)
  • Author(s): Hideki Makishima
  • Organizer: Annual Colloquium (Cancer Course, Kyoto University)
  • Invited
• [Presentation] MOLECULAR PATHOGENESIS OF DISEASE PROGRESSION IN MLLREARRANGED AML. (2018)
  • Author(s): Shinichi Kotani, Keisuke Kataoka, Akinori Yoda, Ayana Kon, et al., Akifumi Takaori-Kondo, Seishi Ogawa, Hideki Makishima.
  • Organizer: 23rd Congress of European Hematology Association (EHA)
  • Int'l Joint Research
• [Presentation] Invariant Patterns of Clonal Succession Determines Specific Phenotypic and Clinical Features of Myelodysplastic Syndromes (MDS). (2018)
  • Author(s): Yasunobu Nagata, Hideki Makishima et al.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Novel and Significant Impact of Germline Variants Predisposed to Pathogenic Somatic Mutations and Loss of Heterozygosity (LOH) in Myelodysplastic Syndromes (MDS) and Clonal Hematopoiesis of Indeterminate Potential (CHIP). (2018)
  • Author(s): Hideki Makishima et al.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Opposing Pathogenesis of Germline SAMD9/SAMD9L Variants in Adult Myelodysplastic Syndrome (MDS). (2018)
  • Author(s): Yasunobu Nagata, Satoshi Narumi, Yihong Guan, Bartlomiej Przychodzen, Cassandra Hirsch, Hideki Makishima et al.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Genomic Analysis of Myelodysplastic Syndromes Among Nagasaki Atomic Bomb Survivors. (2018)
  • Author(s): Masataka Taguchi et al., Hideki Makishima, Yasuhito Nannya, Yukiyoshi Moriuchi, Seishi Ogawa, Koh-ichiro Yoshiura, Yasushi Miyazaki.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Modulation of TET2 Activity By Ascorbic Acid and Factors Affecting Lysine Acetylation. (2018)
  • Author(s): Yihong Guan et al., Hideki Makishima, Aziz Nazha, Daniel Gackowski, Ewelina Zarakowska, Mridul Mukherji, Mikkael Sekeres, Mingjiang Xu, Ryszard linski, Jaroslaw Maciejewsk, Babal Jha.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Pan-Myeloid Leukemia Analysis: Machine Learning-Based Approach to Predict Phenotype and Clinical Outcomes Using Mutation Data. (2018)
  • Author(s): Kiyomi Morita, Feng Wang, Hideki Makishima et al.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Remarks] Researchmap
  • URL: https://researchmap.jp/read0132488/?lang=english