Searching leukemia predisposition gene in bone marrow failure syndrome with functional analysis.

• Project/Area Number: 16K10013
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Yamagata University
• Principal Investigator: Mitsui Tetsuo 山形大学, 医学部, 教授 (30270846)
• Co-Investigator(Kenkyū-buntansha): 早坂 清 山形大学, 医学部, 名誉教授 (20142961) ; 簡野 美弥子 山形大学, 医学部, 助教 (40400551)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: CSF3受容体 / G-CSF受容体切断型異常 / 骨髄機能不全症候群 / 白血病化 / 先天性好中球減少症 / CSF3R / G-CSF受容体 / 切断型遺伝子異常

Outline of Final Research Achievements

The genomic instability in patients with bone marrow failure syndrome was observed in a prospective study. An analysis of G-CSF receptor (CSF3R) gene was done in bone marrow failure syndrome, including congenital neutropenia which is a typical disease reported as progressing myelodysplasia and leukemia. Two somatic gene mutations revealed. One was a heterozygous gene mutation (Ala569Val) immediately above the transmembrane portion of the CSF3 receptor, and the other case was a stop codon case of CSF3R731. The first case had no change in her clinical course, and the mutation was disappeared in the six months later in her bone marrow (BM). The second case showed the 8th and 21st chromosome trisomy clones in his BM simultaneously, and allogeneic hematopoietic cell transplantation was performed. These results demonstrate genomic instability in patients with congenital neutropenia. The spontaneous mutation disappearance was also observed in untreated patients.

Academic Significance and Societal Importance of the Research Achievements

こうした一過性のアミノ酸変化や切断型異常の出現は、先天性好中球減少症の患者さんにおけるゲノム不安定性を実証するもので興味深い。また1例目のものは、無治療経過観察の中で、変異は自然に消滅しており、この観察も意義深いと考えられる。他の解析継続症例にはCSF3Rの遺伝子変異は観られずその臨床経過も大きな変化はなく稀少疾患で長期の観察が必要な疾患群であり、数年という短期の検討では、有意な結果を得る事が困難であることが示された。

Research Products

• [Journal Article] The effect of graft‐versus‐host disease on outcomes after allogeneic stem cell transplantation for refractory lymphoblastic lymphoma in children and young adults (2019)
  • Author(s): Mitsui Tetsuo、Fujita Naoto、Koga Yuhki、Fukano Reiji、Osumi Tomoo、Hama Asahito、Koh Katsuyoshi、Kakuda Harumi、Inoue Masami、Fukuda Takahiro、Yabe Hiromasa、Takita Junko、Shimada Akira、Hashii Yoshiko、Sato Atsushi、Atsuta Yoshiko、Kanda Yoshinobu、Suzumiya Junji、Kobayashi Ryoji
  • Journal Title: Pediatric Blood & Cancer Volume: 67 Issue: 4
  • DOI: 10.1002/pbc.28129
  • Peer Reviewed
• [Journal Article] Three Consecutive Cases of Familial Hemophagocytic Lymphohistiocytosis, Including a Case Due to Maternal Uniparental Disomy. (2019)
  • Author(s): 2.Sato H, Kawasaki N, Kawasaki M, Abiko Y, Meguro T, Takahashi N, Izumino H, Kanno M, Numakura C, Sasaki A, Imamura T, Taki T, Mitsui T.
  • Journal Title: J Pediatr Hematol Oncol. Volume: - Issue: 8 Pages: e819-e821
  • DOI: 10.1097/mph.0000000000001681
  • Peer Reviewed
• [Journal Article] Clinical Features and Prognosis According to Immunophenotypic Subtypes Including the Early T-Cell Precursor Subtype of T-Lymphoblastic Lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study. (2018)
  • Author(s): Fukano R, Sunami S, Sekimizu M, Takimoto T, Mori T, Mitsui T, Mori T, Saito AM, Watanabe T, Ohshima K, Fujimoto J, Nakazawa A, Kiyokawa N, Kobayashi R, Horibe K, Tsurusawa M
  • Journal Title: J Pediatr Hematol Oncol. Volume: 40 Issue: 1 Pages: e34-e37
  • DOI: 10.1097/mph.0000000000000850
  • Peer Reviewed
• [Journal Article] Pediatric follicular lymphoma in Japan. (2017)
  • Author(s): Kobayashi R, Tanaka F, Nakazawa A, Ueyama JI, Sunami S, Mitsui T, Koga Y, Mori T, Osumi T, Fukano R, Ohki K, Sekimizu M, Fujita N, Kamei M, Mori T
  • Journal Title: Int J Hematol Volume: 105 Issue: 6 Pages: 849-853
  • DOI: 10.1007/s12185-017-2209-1
  • Peer Reviewed
• [Journal Article] Prognostic Impact of Intensified Maintenance Therapy on Children With Advanced Lymphoblastic Lymphoma: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study. (2016)
  • Author(s): Sunami S, Sekimizu M, Takimoto T, Mori T, Mitsui T, Fukano R, Saito AM, Watanabe T, Ohshima K, Fujimoto J, Nakazawa A, Kobayashi R, Horibe K, Tsurusawa M
  • Journal Title: Pediatr Blood Cancer Volume: 63 Issue: 3 Pages: 451-7
  • DOI: 10.1002/pbc.25824
  • Peer Reviewed
• [Journal Article] Randomized study of granulocyte colony stimulating factor for childhood B-cell non-Hodgkin lymphoma: a report from the Japanese pediatric leukemia/lymphoma study group B-NHL03 study. (2016)
  • Author(s): Tsurusawa M, Watanabe T, Gosho M, Mori T, Mitsui T, Sunami S, Kobayashi R, Fukano R, Tanaka F, Fujita N, Inada H, Sekimizu M, Koh K, Kosaka Y, Komada Y15, Saito AM, Nakazawa A, Horibe K
  • Journal Title: Leuk Lymphoma. Volume: 57 Pages: 1657-64
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic stem cell transplantation for Chediak-Higashi syndrome. (2016)
  • Author(s): Umeda K, Adachi S, Horikoshi Y, Imai K, Terui K, Endo M, Mitsui T, Kato K, Koh K, Kajiwara R, Ito R, Otsuka Y, Inoue M, Ishii E, Yabe H.
  • Journal Title: Pediatiric Transplant Volume: 20 Issue: 2 Pages: 271-5
  • DOI: 10.1111/petr.12626
  • Peer Reviewed