MEF2D fusions are found in a special subtype of B-cell precursor acute lymphoblastic leukemia(BCP-ALL)with poor prognosis.In this study,we conducted high-throughput drug screenings using cell line and ex vivo cell mod...MEF2D fusions are found in a special subtype of B-cell precursor acute lymphoblastic leukemia(BCP-ALL)with poor prognosis.In this study,we conducted high-throughput drug screenings using cell line and ex vivo cell model harboring,respectively,MEF2D::HNRNPUL1(MH)and MEF2D::BCL9(MB),the two major MEF2D fusions.We identified CUDC-907 as a highly potent dual-target inhibitor of PI3K/HDAC,demonstrating remarkable efficacy in inducing robust lethality while maintaining selectivity for MEF2D fusion-expressing cells.CUDC-907 effectively induced apoptosis and promoted the down-regulation of pre-BCR signaling.We discovered that the hyperactivation of the PI3K-AKT signaling pathway,HDAC9,and BCL2 contributed to the sustained state of MEF2D fusion(+)BCP-ALL.展开更多
基金supported by research grant 82230006,82300167 from the National Natural Science Foundation of Chinathe Overseas Expertise Introduction Project for Discipline Innovation(111 Project,B17029)+4 种基金Shanghai Shenkang Hospital Development Center(No.SHDC2020CR5002)Innovative Research Team of High-level Local Universities in Shanghai,CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-5-010)Yangfan Special Project of Shanghai Science and Technology Innovation Action Plan(23YF1424300)National Key Research and Development Program of China(No.2023YFC2508900)Science and Technology Commission of Shanghai Municipality(No.23141903000).
文摘MEF2D fusions are found in a special subtype of B-cell precursor acute lymphoblastic leukemia(BCP-ALL)with poor prognosis.In this study,we conducted high-throughput drug screenings using cell line and ex vivo cell model harboring,respectively,MEF2D::HNRNPUL1(MH)and MEF2D::BCL9(MB),the two major MEF2D fusions.We identified CUDC-907 as a highly potent dual-target inhibitor of PI3K/HDAC,demonstrating remarkable efficacy in inducing robust lethality while maintaining selectivity for MEF2D fusion-expressing cells.CUDC-907 effectively induced apoptosis and promoted the down-regulation of pre-BCR signaling.We discovered that the hyperactivation of the PI3K-AKT signaling pathway,HDAC9,and BCL2 contributed to the sustained state of MEF2D fusion(+)BCP-ALL.
