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bioRxiv · 10.1101/2024.11.01.621626

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.
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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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Yang, H., Wang, P., Tan, P., Xue, Q., Wu, H., He, K., Wang, B., Wang, D., Ma, T., Ding, S.. 2024-11-04. Reinforced identity confers cells with cancer hallmarks. https://doi.org/10.1101/2024.11.01.621626

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