Functional analysis of novel chimeric gene SNX2-ABL1 detected in childhood acute lymphoblastic leukemia

• Project/Area Number: 25860899
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tokyo University of Science
• Principal Investigator: IIJIMA Kazutoshi 東京理科大学, 工学部, 助教 (30468508)
• Research Collaborator: TOMITA Osamu 順天堂大学, 医学部, 助教 ; SUZUKI Ryo 東京理科大学大学院, 総合化学研究科 ; OCHI Kentaro 東京理科大学, 工学部 ; KOMARU Kanae 東京理科大学, 工学部
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 白血病 / シグナル伝達 / チロシンキナーゼ阻害剤 / B前駆細胞性急性リンパ芽球性白血病 / キメラ遺伝子

Outline of Final Research Achievements

Therapeutic application of tyrosine kinase inhibitors (TKIs) has significantly improved the outcome of BCR-ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Recently, novel ABL1-related chimeric transcripts were identified. In this study, we investigated the functional characteristics of SNX2-ABL1 protein. IL-3-independent proliferative ability was acquired by induction of SNX2-ABL1 as similar as BCR-ABL1 in IL3-dependent mouse pro-B Ba/F3 cells. SNX2-ABL1-expressing Ba/F3 cells showed rather lower sensitivity against TKIs, especially dasatinib. Then, the mechanism of resistance to dasatinib was investigated. As a result, SNX2-ABL1-expressing Ba/F3 cells showed different phosphorylation pattern of those of BCR-ABL1 and the phosphorylation of intracellular proteins, especially CrkL, p44/42 MAPK, STAT5, are only partially inhibited by TKI treatment. From gene expression analysis, high expression of Igf-1 in SNX2-ABL1 expressing cells was observed.

Research Products

• [Journal Article] Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1. (2014)
  • Author(s): Tomita O, Iijima K, Ishibashi T, Osumi T, Kobayashi K, Okita H, Saito M, Mori T, Shimizu T, Kiyokawa N.
  • Journal Title: Leukemia Research Volume: 38 Issue: 3 Pages: 361-370
  • DOI: 10.1016/j.leukres.2013.11.017
  • Peer Reviewed
• [Journal Article] Poor responses to tyrosine kinase inhibitors in a child with precursor B-cell acute lymphoblastic leukemia with SNX2-ABL1 chimeric transcript. (2014)
  • Author(s): Masuzawa A, Kiyotani C, Osumi T, Shioda Y, Iijima K, Tomita O, Nakabayashi K, Oboki K, Yasuda K, Sakamoto H, Ichikawa H, Hata K, Yoshida T, Matsumoto K, Kiyokawa N, Mori T.
  • Journal Title: Eur J Haematol. Volume: 92(3) Issue: 3 Pages: 263-267
  • DOI: 10.1111/ejh.12234
  • Peer Reviewed
• [Presentation] SNX2-ABL1の機能解析とチロシンキナーゼ阻害剤抵抗性機序の解明 (2014)
  • Author(s): 飯島一智, 富田理, 石橋武士, 増澤亜紀, 大隈朋生, 森鉄也, 清河信敬
  • Organizer: 第56回日本小児血液・がん学会学術集会
  • Place of Presentation: 岡山コンベンションセンター
  • Year and Date: 2014-11-28 – 2014-11-30
• [Presentation] Dasatinib抵抗性の白血病新規キメラ分子SNX2-ABL1についての検討 (2014)
  • Author(s): 富田理, 飯島一智, 石橋武士, 大隅朋生, 増澤亜紀, 齋藤正博, 森鉄也, 清河信敬, 清水俊明
  • Organizer: 第117回小児科学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2014-04-11 – 2014-04-13
• [Presentation] キメラ遺伝子を有しない小児BCP-ALL症例の遺伝子発現プロファイルに基づく分類 (2013)
  • Author(s): 飯島一智, 清河信敬, 吉原宏樹, 大隅朋生, 加藤元博, 小林健一郎, 大喜多肇, 藤本純一郎, 花田良二, 土田昌宏, 嶋田博之, 福島敬, 康勝好, 真部淳, 菊地陽, 林泰秀, 小原明
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] SNX2-ABL1融合遺伝子陽性小児B前駆細胞性急性リンパ性白血病：症例報告 (2013)
  • Author(s): 増澤 亜紀, 清谷 知賀子, 飯島 一智, 富田 理, 大隅 朋生, 寺島 慶太, 山崎 文登, 弦間 友紀, 宇野光昭, 塩田 曜子, 清河 信敬, 森 鉄也
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] BCP-ALLの新規キメラ分子SNX2-ABL1の機能解析 (2013)
  • Author(s): 富田理, 飯島一智, 石橋武士, 大隅朋生, 増澤亜紀, 清谷知賀子, 斎藤正博, 森鉄也, 清水俊明, 清河信敬
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
• [Presentation] 小児Ph-like ALL症例の表面マーカー、遺伝子発現解析 (2013)
  • Author(s): 飯島一智, 清河信敬, 吉原宏樹, 富田理, 小林健一郎, 福島敬, 林泰秀, 菊地陽, 康勝好, 真部淳, 小原明
  • Organizer: 第55回日本小児血液・がん学会学術集会
  • Place of Presentation: 博多
• [Presentation] BCP-ALLの新規キメラ分子SNX2-ABL1の機能解析とチロシンキナーゼ阻害剤に対する感受性についての検討 (2013)
  • Author(s): 富田理, 飯島一智, 石橋武士, 増澤亜紀, 大隅朋生, 斎藤正博, 森鉄也, 清水俊明, 清河信敬
  • Organizer: 第55回日本小児血液・がん学会学術集会
  • Place of Presentation: 博多