3170 – SINGLE-CELL MULTI-OMICS RESOLVES THE EVOLUTION OF TP53-MUTANT LEUKEMIA

Alba Rodriguez-Meira*, Ruggiero Norfo, Wei Wen, Agathe Chedeville, Haseeb Rahman, Jennifer O'Sullivan, Guanlin Wang, Eleni Louka, Warren Kretzschmar, Aimee Paterson, Charlotte Brierley, Jean-Edouard Martin, Caroline Demeule, Matthew Bashton, Nikolaos Sousos, Angela Hamblin, Helene Guermouche, Florence Pasquier, Christophe Marzac, François GirodonMark Drummond, Claire Harrison, Isabelle Plo, Sten Eirik Jacobsen, Bethan Psaila, Supat Thongjuea, Iléana Antony-Debré, Adam Mead

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

TP53 regulates self-renewal and quiescence of hematopoietic stem cells, and its disruption leads to the development of hematological malignancies. In myeloid neoplasms, TP53 mutations define a distinct clinical entity, associated with complex cytogenetics and dismal outcomes. Understanding the cellular and molecular framework through which TP53 mutation drives clonal evolution is a crucial step towards the design of rational therapeutic strategies. Here, we carry out TARGET-seq single-cell multi-omic analysis of haematopoietic stem/progenitor cells (HSPC) from patients with a myeloproliferative neoplasm who had transformed to TP53-mutant secondary acute myeloid leukaemia (sAML), a trackable model of TP53-driven clonal evolution. We invariably identified convergent clonal evolution leading to complete loss of TP53 wild-type (WT) alleles and gain of multiple chromosomal abnormalities upon transformation. TP53-mutant leukaemia stem cells (LSC) were transcriptionally distinct from de novo AML, with evidence of inflammation-associated transcription and aberrant erythroid differentiation. We identified a TP53-mutant LSC signature which was strongly predictive of adverse outcome in both TP53-mutant (HR:3.4) and WT AML (HR:3.1). Finally, we demonstrate a hitherto unrecognised effect of chronic inflammation in promoting disease progression. Sustained inflammatory stimuli (pIpC) led to a 2.5-fold expansion of TP53-mutant cells in WT:TP53R172H/+ chimeras, whereas WT cells were depleted. This indicates that pro-inflammatory cues promote fitness advantage of TP53-mutant cells whilst suppressing antecedent clones. In summary, we present a comprehensive single-cell multi-omic analysis ofTP53-mediated transformation, providing unique insights into the evolution of chronic hematological malignancies towards an aggressive acute leukemia and of broader relevance to other cancer types.
Original languageEnglish
Pages (from-to)S129-S130
Number of pages2
JournalExperimental Hematology
Volume111
Issue numberSupplement
Early online date18 Oct 2022
DOIs
Publication statusPublished - 2022

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