Molecular pathogenesis of familial myelodysplastic syndromes

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09831
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tokyo Metropolitan Komagome Hospital (Clinical research laboratory) (2018); Bunkyo Gakuin University (2016-2017)
• Principal Investigator: HARADA Yuka 東京都立駒込病院(臨床研究室), 臨床試験科, 医長 (50379848)
• Co-Investigator(Kenkyū-buntansha): 原田 浩徳 東京薬科大学, 生命科学部, 教授 (10314775)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 家族性造血器腫瘍 / 骨髄異形成症候群（MDS） / ターゲットシークエンス / RUNX1変異 / TP53変異 / マウス骨髄移植モデル

Outline of Final Research Achievements

Germline predisposition is increasingly recognized in myelodysplastic syndromes (MDS). We found 20 pedigrees of myeloid neoplasms and analyzed the mutations of RUNX1, CEBPA, GATA2 and DDX41 genes. Using Sanger sequencing and target sequencing by next generation sequencing, only 6 pedigrees were identified their responsible gene mutations. The responsible gene mutations could not be identified in other 14 pedigrees, suggesting that there still may exist many potential pedigrees of familial myeloid neoplasms caused by unknown gene mutations.
We identified a collaboration partner gene, Gene Y, which was detected in iPS cells from RUNX1-mutated pedigree. Co-transduction of a RUNX1-mutant and Gene Y in mouse bone marrow transplantation model developed MDS with severe anemia in a few months. Therefore, we suspected that a RUNX1 mutation is one of the stem cell aging factors.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

家族性造血器腫瘍20家系のうち、既知の原因遺伝子のうちいずれかの変異を認めた家系は少数にとどまり、大半の症例で原因遺伝子変異が同定されなかったことから、germline変異の原因遺伝子変異として知られているものは一部に過ぎず、潜在的に多くの家系が未知の遺伝子異常により家族性造血器腫瘍を発症していることが示唆された。また、RUNX1変異自体が分化障害を有し、Gene Yと協調して非常に短期間でMDSを発症することから、RUNX1変異自体がエイジング因子であると考えられた。