| Project/Area Number |
18K16083
|
|---|
| Research Category |
Grant-in-Aid for Early-Career Scientists
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Basic Section 54010:Hematology and medical oncology-related
|
|---|
| Research Institution | Nagoya University |
|---|
Principal Investigator |
Okuno Yusuke 名古屋大学, 医学部附属病院, 病院講師 (00725533)
|
|---|
| Project Period (FY) |
2018-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
|
|---|
| Keywords | 急性リンパ性白血病 / 小児がん / MEF2D融合遺伝子 / ステロイド抵抗性 / 次世代シークエンス / 薬剤感受性 |
|---|
| Outline of Final Research Achievements |
Acute lymphoblastic leukemia (ALL) is the most common neoplasm in children. The MEF2D fusion genes have been identified as a causative chromosomal aberration in ALL. Patients with ALL carrying the MEF2D fusion genes (MEF2D-ALL) have shown resistance to corticosteroid chemotherapy. We performed a global expression analysis of MEF2D-ALL blasts in the presence of corticosteroids and found that intracellular steroid signaling was insufficient to induce cell death. In a fraction of patients with MEF2D-ALL, this insufficiency was caused by a deletion of the NR3C1 steroid receptor gene and/or a deletion of the IKZF1 gene, which are known causes of corticosteroid resistance. In the remaining patients, NR3C1 expression was also significantly decreased. In conclusion, patients carrying MEF2D-ALL have corticosteroid resistance, which was caused by way of a decreased NR3C1 expression.
|
| Academic Significance and Societal Importance of the Research Achievements |
MEF2D融合遺伝子を持つALL(MEF2D-ALL)は、2016年に私たちの研究グループを含めた複数のグループが発見した新たなALLである。ALL全体の長期生存率は90%に達しているが、アジアにおけるMEF2D-ALLの治療成績は25%未満であり、非常に予後が悪い一群である。私たちの研究グループは、MEF2D-ALLの予後が悪い原因の1つとして、ALL治療の鍵となる抗がん剤であるステロイド薬が全く作用しないこと(ステロイド抵抗性)を明らかにした。このALLにおけるステロイド抵抗性の機序は今回の研究によりかなり明らかになったが、ステロイド抵抗性を解除し、治癒に導く方法の開発が必要である。
|
