Significance of BCR gene breakpoint in Ph + ALL

• Project/Area Number: 17K16186
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: NISHIWAKI Satoshi 名古屋大学, 医学部附属病院, 講師 (80753037)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: フィラデルフィア染色体陽性急性リンパ性白血病 / BCR切断点 / BCR-ABL融合遺伝子 / 血球系統 / BCR遺伝子切断点 / 好中球FISH / 組織FISH / 内科 / 血液内科学 / 血液腫瘍学

Outline of Final Research Achievements

Multi-lineage BCR-ABL expression (Multi-Ph) was defined in 21 of 59 patients (36%). BCR breakpoint was major in 17 of 21 Multi-Ph (81%). In such patients, BCR-ABL was detected at the multipotent progenitor level. However, no IKZF1 deletion patterns that were specific for Multi-Ph were identified. On the other hand, better survival rates were observed in patients with Multi-Ph compared with survival rates in those with uni-lineage BCR-ABL expression. In multivariate analyses, Multi-Ph was identified as a good prognostic factor for both overall survival and event-free survival. We confirmed Multi-Ph in more than one-third of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Although no specific molecular characteristics were identified, Multi-Ph was associated with better treatment outcomes.

Academic Significance and Societal Importance of the Research Achievements

フィラデルフィア染色体陽性急性リンパ性白血病(Ph+ALL)においてBCR-ABL融合遺伝子が白血病芽球以外に発現している例が3分の１以上と一定の割合であることを示した。さらに、発現系統の違いが治療成績とも関連があり、BCR-ABL融合遺伝子が白血病芽球以外に発現していることが予後良好と関連することを示した。このことは、Ph+ALLにおける新たな予後因子としてBCR-ABL融合遺伝子の発現血球系統の違いが有用であることを示唆している。さらに背景にあると思われる遺伝子異常等の違いを明らかにすることでPh＋ALLの層別化につながると考えられる。

Research Products

• [Journal Article] Multi-Lineage BCR-ABL Expression in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Associated With Improved Prognosis but No Specific Molecular Features (2020)
  • Author(s): Nishiwaki S, Kim JH, Ito M, Maeda M, Okuno Y, Koyama D, Ozawa Y, Gunji M, Osaki M, Kitamura K, Ushijima Y, Ishikawa Y, Miyamura K, Sugiura I, Kiyoi H
  • Journal Title: Frontiers in Oncology Volume: 10 Pages: 586567-586567
  • DOI: 10.3389/fonc.2020.586567
  • Peer Reviewed / Open Access
• [Journal Article] A consideration for efficient unrelated hematopoietic stem cell source acquisition-from an experience of Japan. (2020)
  • Author(s): Nishiwaki S, Miyamura K, Kanda Y, Takanashi M, Uchida N, Fukuda T, Ikegame K, Ohashi K, Eto T, Ozawa Y, Shiratori S, Iwato K, Matsuoka KI, Hidaka M, Ichinohe T, Atsuta Y, Kodera Y, Okamoto S
  • Journal Title: Bone Marrow Transplantation Volume: 55 Issue: 3 Pages: 657-660
  • DOI: 10.1038/s41409-019-0542-0
  • Peer Reviewed
• [Journal Article] Different impact of BCR-ABL transcripts on allogeneic hematopoietic cell transplantation from different graft sources for Ph+ALL with minimal residual disease. (2019)
  • Author(s): Nishiwaki S, Mizuta S, Ohashi K, Fukuda T, Uchida N, Tachibana T, Onizuka M, Ozawa Y, Onishi Y, Takahashi S, Eto T, Nakamae H, Tanaka J, Ichinohe T, Atsuta Y, Kako S
  • Journal Title: American Journal of Hematology Volume: 94 Issue: 11
  • DOI: 10.1002/ajh.25612
  • Peer Reviewed
• [Journal Article] Tyrosine kinase inhibitor prophylaxis after transplant for Philadelphia chromosome-positive acute lymphoblastic leukemia. (2019)
  • Author(s): Akahoshi Y, Nishiwaki S, Mizuta S, Ohashi K, Uchida N, Tanaka M, Fukuda T, Ozawa Y, Takahashi S, Onizuka M, Shiratori S, Nakamae H, Kanda Y, Ichinohe T, Atsuta Y, Kako S
  • Journal Title: Cancer Science Volume: 110 Issue: 10 Pages: 3255-3266
  • DOI: 10.1111/cas.14167
  • Peer Reviewed / Open Access
• [Journal Article] Availability of HLA-allele-matched unrelated donors: estimation from haplotype frequency in the Japanese population. (2019)
  • Author(s): Nishiwaki S, Tanaka H, Kojima H, Okamoto S
  • Journal Title: Bone Marrow Transplantation Volume: 54 Issue: 2 Pages: 300-303
  • DOI: 10.1038/s41409-018-0263-9
  • Peer Reviewed
• [Journal Article] Phase I study of cord blood transplantation with intrabone marrow injection of mesenchymal stem cells: A clinical study protocol (2018)
  • Author(s): Goto T, Murata M, Terakura S, Nishida T, Adachi Y, Ushijima Y, Shimada K, Ishikawa Y, Hayakawa F, Nishio N, Nishiwaki S, Hirakawa A, Kato K, Takahashi Y, Kiyoi H
  • Journal Title: Medicine Volume: 97 Issue: 17 Pages: e0449-e0449
  • DOI: 10.1097/md.0000000000010449
  • Peer Reviewed / Open Access
• [Journal Article] Successful treatment with allogeneic stem cell transplantation followed by DLI and TKIs for e6a2 BCR-ABL-positive acute myeloid leukaemia: A case report and literature review. (2017)
  • Author(s): Harada Y, Nishiwaki S, Sugimoto T, Onodera K, Goto T, Sato T, Kamoshita S, Kawashima N, Seto A, Okuno S, Yamamoto S, Iwasaki T, Ozawa Y, Miyamura K, Akatsuka Y, Sugiura I
  • Journal Title: Medicine Volume: 96 Issue: 50 Pages: e9160-e9160
  • DOI: 10.1097/md.0000000000009160
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of autologous peripheral blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia: A study protocol for a multicenter exploratory prospective study (Auto-Ph17 study). (2017)
  • Author(s): Nishiwaki S, Sugiura I, Miyata Y, Saito S, Sawa M, Nishida T, Miyamura K, Kuwatsuka Y, Kohno A, Yuge M, Kasai M, Iida H, Kurahashi S, Osaki M, Goto T, Terakura S, Murata M, Nishikawa H, Kiyoi H
  • Journal Title: Medicine Volume: 96 Issue: 52 Pages: e9568-e9568
  • DOI: 10.1097/md.0000000000009568
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Synchronous Multiple Primary Malignant Tumors on Newly Diagnosed Hematological Malignancies. (2017)
  • Author(s): Nishiwaki S, Okuno S, Suzuki K, Kurahashi S, Sugiura I
  • Journal Title: Clinical lymphoma, myeloma & leukemia Volume: 17 Issue: 12 Pages: e79-e85
  • DOI: 10.1016/j.clml.2017.09.006
  • NAID: 120006383810
  • Peer Reviewed
• [Journal Article] Effective chemomobilization with etoposide and cytarabine (EC regimen) in lymphoma patients: a single-center, retrospective, observational study. (2017)
  • Author(s): Koyama D, Nishiwaki S, Harada Y, Yamamoto S, Kurahashi S, Sugimoto T, Iwasaki T, Sugiura I
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 47 Issue: 9 Pages: 820-825
  • DOI: 10.1093/jjco/hyx076
  • Peer Reviewed
• [Journal Article] Increase of bone marrow macrophages and CD8+ T lymphocytes predict graft failure after allogeneic bone marrow or cord blood transplantation. (2017)
  • Author(s): Kawashima N, Terakura S, Nishiwaki S, Koyama D, Ozawa Y, Ito M, Miyamura K
  • Journal Title: Bone Marrow Transplantation Volume: 52 Issue: 8 Pages: 1164-1170
  • DOI: 10.1038/bmt.2017.58
  • Peer Reviewed
• [Presentation] DIFFERENT IMPACT OF BCR BREAKPOINT ON THE OUTCOME OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FROM DIFFERENT GRAFT SOURCE FOR PH+ALL IN THE ERA OF TKI (2019)
  • Author(s): Satoshi Nishiwaki, Shuichi Mizuta, Kazuteru Ohashi, Takahiro Fukuda, Naoyuki Uchida, Heiwa Kanamori, Makoto Onizuka, Yukiyasu Ozawa, Junji Tanaka, Tatsuo Ichinohe, Yoshiko Atsuta, Shinichi Kako
  • Organizer: 24th Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] TKI時代のPh+ALLに対する同種移植においてBCR切断点の影響が非血縁者間移植ソースにより異なる (2019)
  • Author(s): Satoshi Nishiwaki, Shuichi Mizuta, Kazuteru Ohashi, Takahiro Fukuda, Naoyuki Uchida, Heiwa Kanamori, Makoto Onizuka, Yukiyasu Ozawa, Junji Tanaka, Tatsuo Ichinohe, Yoshiko Atsuta, Shinichi Kako
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 移植実績に基づく同種造血幹細胞移植細胞ソースの入手に関する検証 (2019)
  • Author(s): 西脇聡史、宮村耕一、神田善伸、高梨美乃子、内田直之、福田隆浩、池亀和博、大橋一輝、衛藤徹也、小澤幸泰、一戸辰夫、熱田由子、岡本真一郎
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] 移植実績をもとにした最適なドナープール数を検証するための推計モデルの検討 (2018)
  • Author(s): 西脇 聡史
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] Prognostic impact of synchronous multiple primary malignant tumors on newly diagnosed hematological malignancies. (2017)
  • Author(s): Nishiwaki S
  • Organizer: ESMO Asia 2017
  • Int'l Joint Research
• [Presentation] 名古屋大学医学部附属病院における患者申出療養～「チオテパを用いた自家末梢血幹細胞移植療法」の経験を中心に (2017)
  • Author(s): 西脇 聡史
  • Organizer: 第15回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] 新規悪性リンパ腫患者における診断時重複癌の予後への影響の検討 (2017)
  • Author(s): 西脇 聡史
  • Organizer: 第15回日本臨床腫瘍学会学術集会
• [Presentation] 研究者が特定臨床研究を立ち上げる意欲を高めるための病院としての取り組み (2017)
  • Author(s): 西脇 聡史
  • Organizer: ARO協議会 第5回学術集会
  • Invited