突变体
Wnt信号通路
甲戊酸途径
细胞生物学
生物
计算生物学
遗传学
信号转导
基因
生物合成
作者
Jan Mueller,Roman Schimmer,Christian Koch,Florin Schneiter,Jonas Fullin,Veronika Lysenko,Christian Pellegrino,Nancy Klemm,Norman F. Russkamp,Renier Myburgh,Laura Volta,Alexandre Theocharides,Kari J. Kurppa,Benjamin L. Ebert,Timm Schroeder,Markus G. Manz,Steffen Boettcher
标识
DOI:10.1038/s44321-024-00024-2
摘要
TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are inefficient to control AML cell outgrowth in vitro and in vivo compared to TP53 wild-type cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.
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