Reinforced identity confers cells with cancer hallmarks
Yang, H.; Wang, P.; Tan, P.; Xue, Q.; Wu, H.; He, K.; Wang, B.; Wang, D.; Ma, T.; Ding, S.
Show abstract
Genetic alterations trigger tumorigenesis in a cell type-specific manner, but the biological basis for this, remains unclear. Here we define reinforced original cell identity established by interaction between genetic alterations and original cell type is a pivotal determinant of tumor development. Using AML-M5MLL-AF9 as a model system, we demonstrated that MLL-AF9 enhanced key transcriptional factors (TFs) expression of promonocyte and cooperated with them to amplify their downstream programs for AML hallmarks. Interactions between MLL-AF9 and promonocyte endowed cancer cells with a reinforced promonocyte identity. Reinforced intrinsic cell identity also sustained cancer hallmarks across cancer types. Furthermore, we identified narciclasine, as an effective disruptor of reinforced promonocyte identity, effectively treating AML-M5MLL-AF9. This study not only identified reinforced cell identity as a fundamental tumor driver beyond genetic mutations but also offers a proof-of-concept for reinforced identity- targeted cancer therapy.
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