Study on regulation of lymphocyte development by IKZF family proteins and on molecular pathogenesis of disorders caused by a mutation in IKZF family molecules.
| Project/Area Number |
18H02778
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
|
|---|
| Research Institution | Tokyo Medical and Dental University |
|---|
Principal Investigator |
Morio Tomohiro 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30239628)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
大津 真 東京大学, 医科学研究所, 准教授 (30361330)
|
|---|
| Project Period (FY) |
2018-04-01 – 2021-03-31
|
| Project Status |
Completed (Fiscal Year 2020)
|
| Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2018: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
|
|---|
| Keywords | Ikarosファミリー分子 / 原発性免疫不全症 / リンパ球分化 / 転写調節 / 腫瘍発生 / ヘテロマー干渉阻害 / Neomorph / 遺伝子 / 免疫学 / 臨床 |
|---|
| Outline of Final Research Achievements |
We have identified a human impaired immune disorder with a heterozygous IKZF3 G159R missense variant. The patient developed malignant lymphoma with split BCL6 and loss of NOTCH2. Knock-in (KI) model mice harboring Ikzf3 G158R variant recapitulated the B and T cell phenotypes of the patient. B cell defect was proven to be caused by Ikzf3 variant itself using bone marrow competition assay. IKZF3 G159R was shown to be loss-of-function mutant by EMSA and Luciferase reporter gene assay. Using thymocytes of the KI mice, we showed Ikzf3 G158R lost a capacity to bind to a canonical Ikzf3 DNA sequence; and Ikzf1/Ikzf3 G158R heterodimers did not bind to the canonical Ikzf1/Ikzf3 DNA sequence. The heterodimer also gained affinity to novel DNA sequences. These data indicated that the adaptive immunity defect was caused by the IKZF3 variant hijacking IKZF1 function. This heteromeric interference can be a novel mechanism of autosomal dominance.
|
| Academic Significance and Societal Importance of the Research Achievements |
転写因子の変異では、その変異部位によって様々な表現型を呈することが知られている。研究ではIKZF3の変異が、IKZF1の機能を阻害するという新しい知見をえた。ヘテロマー干渉阻害と名付けた分子機構自体が、新しい概念である。生体内の数多くの分子は複合体を形成して機能していることを鑑みると、変異部位や種類によって、変異分子だけでなく複合体全体の機能に影響が及ぼされることが容易に想像される。この分子機構、ヘテロマー干渉阻害が当てはまる疾患はこれから数多く発見される可能性がある。治療の観点からは、ヘテロマー形成を阻害する方策が考えられ、今後の治療開発戦略にも有用な視点を与えると考えている。
|
Report
(4 results)
Research Products
(8 results)
-
-
-
[Journal Article] A Variant in Human AIOLOS Impairs Adaptive Immunity by interfering with IKAROS.2021
Author(s)
Yamashita M, Kuehn H、Okuyama SK, Okada S, Inoue Y, Mitsuiki N, Imai K, Takagi M, Kanegane H, Takeuchi M, Shimojyo N, Tsumura M, Padhi AK, Zhang KYJ, Boisson B, Casanova JK, Ohara O, Rosenzweig SD, Taniuchi I, and Morio T.
-
Journal Title
Nature Immunology
Volume: accepted
Related Report
Peer Reviewed
-
-
-
[Presentation] A germline AIOLOS variant is associated with abnormal T and B differentiation, pneumocystis pneumonia and increased risk for chronic lymphocytic leukemia(Late Breaker session).2021
Author(s)
Kuehn H, Yamashita M, Niemela JE, Stoddard J, Baxter R, Hsieh E, Garofalo M, Fleisher TA, Morio T, Dutmer C, and Rosenzweig SD.
Organizer
Clinical Immunology Society Meeting
Related Report
Int'l Joint Research
-
-
