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Analysis of mechanisms underlying preferential commitment of hematopoietic stem cells with del(13q) in patients with autoimmune hematopoietic failure

Research Project

Project/Area Number 17K09947
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionKanazawa University

Principal Investigator

Ishiyama Ken  金沢大学, 附属病院, 講師 (60377380)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords自己免疫性造血不全 / 13番染色体長腕の部分欠失(del(13q)) / OLFM4 / TGF-β / 赤血球分化 / CD109 / 13番染色体長腕の部分欠失(del(13q) / LRCH1 / 血液免疫学
Outline of Final Research Achievements

To clarify a role of OLFM4, a gene located in the commonly deleted region of 13q, in the preferential commitment of hematopoietic stem cells (HSCs) with del(13q) in patients with autoimmune hematopoietic failure, we examined the effects of OLFM4 knockout or knockdown in a leukemia cell line TF-1 and CD34+ cells derived from iPS cells or from cord blood. The OLFM4 gene downregulation promoted erythroid differentiation of both TF-1 and CD34+ cells induced by TGF-β. Similarly augmented erythroid differentiation was observed in HSCs that underwent the knockout of a GPI-anchored protein CD109. Haploinsufficiency of OLFM4 as a result of del(13q) may thus explain the preferential commitment of HSCs with del(13q) in bone marrow failure patients with paroxysmal nocturnal hemoglobinuria-phenotype cells.

Academic Significance and Societal Importance of the Research Achievements

del(13q)という染色体異常を持つ再生不良性貧血患者では、なぜ例外なくPNH型血球が検出されるのは不明であった。今回の検討により、del(13q)により生じたOLFM4遺伝子のハプロ不全が、PIGA変異と同様に、造血幹細胞のTGF-βに対する感受性を高め、その結果として、del(13q)陽性血球とPNH形質の血球が検出されやすくなることが、初めて示唆された。その結果として、PNH型血球の増加に、PIGA変異造血幹細胞のTGF-βに対する感受性の低下が関与していることも明らかになった。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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