Genetic alterations of aggressive NK cell leukemia and identification of molecular target candidates

• Project/Area Number: 15K09471
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Shinshu University
• Principal Investigator: ISHIDA FUMIHIRO 信州大学, 学術研究院保健学系, 教授 (80311695)
• Co-Investigator(Renkei-kenkyūsha): SEKIGUCHI Nodoka 信州大学, 学術研究院医学系(医学部附属病院), 講師 (80720953)
• Research Collaborator: OHSHIMA Koichi 久留米大学, 医学部, 教授 (50203766) ; SUZUMIYA Junji 島根大学, 医学部, 教授 (70206556) ; MUSTJOKI Satu ヘルシンキ大学, 血液学研究ユニット, 教授 ; KIM Wong Seog ソンギョングァン大学, 医学部, 教授
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: JAK-STAT系 / NK細胞腫瘍 / 分子標的 / NK細胞白血病 / JAK/STAT系 / 遺伝子変異 / NK細胞 / 遺伝子異常 / 悪性リンパ腫

Outline of Final Research Achievements

Aggressive NK cell leukemia (ANKL) is a malignant hematological disease with poor prognosis which is rare but rather common in young Eastern Asian populations. Diagnostic and therapeutic strategies for ANKL have not been well defined. To elucidate pathogenesis of ANKL and develop novel molecular targets for ANKL, we performed whole-exome sequence analyses of ANKL cells from patients with ANKL. Genetic alterations of several signaling pathways including JAK-STAT and RAS-MAPK, as well as DDX3X and epigenetic modifiers, were identified. Cell lines derived from NK cell malignancies were sensitive to JAK inhibitors, which further demonstrated the importance of JAK-STAT system in the pathogenesis of ANKL. These results provide further insights into molecular pathogenesis of ANKL and target candidates for therapies of NK cell malignancies.

Research Products

• [Int'l Joint Research] ヘルシンキ大学(フィンランド)
• [Int'l Joint Research] サムソンメディカルセンター(韓国)
• [Int'l Joint Research] シティオブホープ国立医学研究所/ヴァージニア大学(米国)
• [Int'l Joint Research] サムソンメディカルセンター(韓国)
• [Int'l Joint Research] ヘルシンキ大学(フィンランド)
• [Int'l Joint Research] ヘルシンキ大学(フィンランド)
• [Int'l Joint Research] サムソンメディカルセンター(韓国)
• [Journal Article] Mutational landscape of aggressive natural killer-cell leukemia and drug profiling highlight JAK-STAT signaling as a therapeutic target in natural killer-cell malignancies (2018)
  • Author(s): Dufva O, Kankainen M, Kelkka T, Sekiguchi N, Awad S, Eldfors S, Yadav B, Kuusanmaki H, Malani D, Andersson E, Pietarinen P, Saikko L, Kovanen P, Ojala T, Lee D, Loughran TJr., Nakazawa H, Suzumiya J, Suzuki R, Ko YH, Kim W, Chuang SS, Aittokallio T, Chan WC, Ohshima K, Ishida F, Mustjoki S
  • Journal Title: Nature Communications Volume: 9 Issue: 1
  • DOI: 10.1038/s41467-018-03987-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell size variations of large granular lymphocyte leukemia; Implication of a small cell subtype of granular lymphocyte leukemia with STAT3 mutations. (2016)
  • Author(s): Tanahashi T, Sekiguchi N, Matsuda K, Takezawa Y, Ito T, Kobayashi H, Ichikawa N, Nishina S, Senoo N, Sakai H, Nakazawa H, Ishida F.
  • Journal Title: Leukemia Res Volume: 45 Pages: 8-13
  • DOI: 10.1016/j.leukres.2016.04.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia. (2016)
  • Author(s): Andersson E, Tanahashi T, Sekiguchi N, Gasparini VR, Bortoluzzi S, Kawakami T, Matsuda K, Mitsui T, Eldfors S, Bortoluzzi S, Coppe A, Binatti A, Lagstrom S,Ellonen P, Fukushima N, Nishina S, Senoo N, Sakai H, Nakazawa H, Kwong YL, Loughran TP, Maciejewski JP, Mustjoki S, Ishida F.
  • Journal Title: Blood Volume: 128 Issue: 20 Pages: 2465-2468
  • DOI: 10.1182/blood-2016-06-724856
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Mutational Landscape of Aggressive Natural Killer Cell Leukemia and Drug Sensitivity Profiling Reveal Therapeutic Options in Natural Killer Cell Malignancies (2016)
  • Author(s): Dufva O, Kankainen K, Kelkka T, Awad SA, Sekiguchi N, Yadav B, Eldfors S, Kuusanm H, Andersson EI, Malani D, Pietarinen P, Saikko L, Kovanen PE, Suzumiya J, Suzuki R, Ko YH, Kim WS, Chuang SS, Loughran TPJr, Chan WC, Ohshima K, Aittokallio T, Ishida F, Mustjoki S
  • Organizer: 58th American Society of Hematology Annual Meeting & Exposition
  • Place of Presentation: 米国サンディエゴ市
  • Year and Date: 2016-12-03