Deciphering TP53 mutant Cancer Evolution with Single-Cell Multi-Omics

Rodriguez-Meira, A.; Norfo, R.; Wen, W. X.; Chedeville, A. L.; Rahman, H.; OSullivan, J.; Wang, G.; Louka, E.; Kretzschmar, W.; Paterson, A.; Brierley, C.; Martin, J.-E.; Demeule, C.; Bashton, M.; Sousos, N.; Hamblin, A.; Guermouche, H.; Pasquier, F.; Marzac, C.; Girodon, F.; Drummond, M.; Harrison, C.; Plo, I.; Jacobsen, S. E. W.; Psaila, B.; Thongjuea, S.; Antony-Debre, I.; Mead, A. J.

doi:10.1101/2022.03.28.485984

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bioRxiv · 10.1101/2022.03.28.485984

Deciphering TP53 mutant Cancer Evolution with Single-Cell Multi-Omics

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Abstract

TP53 is the most commonly mutated gene in human cancer, typically occurring in association with complex cytogenetics and dismal outcomes. Understanding the genetic and non-genetic determinants of TP53-mutation driven clonal evolution and subsequent transformation is a crucial step towards the design of rational therapeutic strategies. Here, we carry out allelic resolution single-cell multi-omic analysis of haematopoietic stem/progenitor cells (HSPC) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukaemia (AML), a tractable model of TP53-mutant cancer evolution. All patients showed dominant TP53 multi-hit HSPC clones at transformation, with a leukaemia stem cell transcriptional signature strongly predictive of adverse outcome in independent cohorts, across both TP53-mutant and wild-type AML. Through analysis of serial samples and antecedent TP53-heterozygous clones, we demonstrate a hitherto unrecognised effect of chronic inflammation, which supressed TP53 wild-type HSPC whilst enhancing the fitness advantage of TP53 mutant cells. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukaemia, and are of broader relevance to other cancer types.

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Rodriguez-Meira, A., Norfo, R., Wen, W. X., Chedeville, A. L., Rahman, H., OSullivan, J., Wang, G., Louka, E., Kretzschmar, W., Paterson, A., Brierley, C., Martin, J.-E., Demeule, C., Bashton, M., Sousos, N., Hamblin, A., Guermouche, H., Pasquier, F., Marzac, C., Girodon, F., Drummond, M., Harrison, C., Plo, I., Jacobsen, S. E. W., Psaila, B., Thongjuea, S., Antony-Debre, I., Mead, A. J.. 2022-03-29. Deciphering TP53 mutant Cancer Evolution with Single-Cell Multi-Omics. https://doi.org/10.1101/2022.03.28.485984

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