Elucidation of mechanism of methylation by PTPN11 mutation in juvenile myelomonocytic leukemia

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08368
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Shinshu University
• Principal Investigator: Matsuda Kazuyuki 信州大学, 学術研究院保健学系, 教授 (00647084)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 若年性骨髄単球性白血病 / PTPN11 / メチル化 / iPS細胞 / ゲノム改変

Outline of Final Research Achievements

The aim of this study was to clarify the effect of PTPN11 mutation, which is frequently observed in juvenile myelomonocytic leukemia (JMML), on methylation. CD34-positive cells were induced to differentiate using JMML-derived iPS cells that differ only in the presence or absence of the PTPN11 mutation, and iPS cells that were mutation-repaired or mutagenized by genomic modification. Efficient induction of differentiation into CD34-positive cells and extraction of high-concentration genomic DNA from the cells enabled us to perform comprehensive methylation analysis. The results revealed a group of genes whose methylation rate increased or decreased depending on the presence or absence of PTPN11 mutation. Further studies are needed to elucidate the mechanism of methylation regulation by PTPN11 mutation.

Free Research Field

血液疾患における遺伝子、染色体解析

Academic Significance and Societal Importance of the Research Achievements

JMML由来のiPS細胞を用いた研究は、細胞株のないJMMLの病態解明に寄与できると考えられる。本研究ではPTPN11変異有無のみ異なるiPS細胞から分化誘導したCD34陽性細胞を使用した網羅的メチル化解析を行い、直接的にPTPN11変異の有無によるメチル化への影響について解析した。変異陽性（導入）細胞でメチル化率が増加する遺伝子群と変異陰性（修復）細胞でメチル化率が増加する遺伝子群を明らかになり、今後、これらの遺伝子の機能分類を行うと伴にPTPN11変異によるメチル化調節機構の解明を行うで難治性のJMMLの新たな治療薬等の開発につながる可能性もある。