Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution

Alba Rodriguez-Meira; Ruggiero Norfo; Sean Wen; Agathe L. Chédeville; Haseeb Rahman; Jennifer O’Sullivan; Guanlin Wang; Eleni Louka; Warren W. Kretzschmar; Aimee Paterson; Charlotte Brierley; Jean Edouard Martin; Caroline Demeule; Matthew Bashton; Nikolaos Sousos; Daniela Moralli; Lamia Subha Meem; Joana Carrelha; Bishan Wu; Angela Hamblin; Helene Guermouche; Florence Pasquier; Christophe Marzac; François Girodon; William Vainchenker; Mark Drummond; Claire Harrison; J. Ross Chapman; Isabelle Plo; Sten Eirik W. Jacobsen; Bethan Psaila; Supat Thongjuea; Iléana Antony-Debré; Adam J. Mead

doi:10.1038/s41588-023-01480-1

Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution

Alba Rodriguez-Meira, Ruggiero Norfo, Sean Wen, Agathe L. Chédeville, Haseeb Rahman, Jennifer O’Sullivan, Guanlin Wang, Eleni Louka, Warren W. Kretzschmar, Aimee Paterson, Charlotte Brierley, Jean Edouard Martin, Caroline Demeule, Matthew Bashton, Nikolaos Sousos, Daniela Moralli, Lamia Subha Meem, Joana Carrelha, Bishan Wu, Angela HamblinHelene Guermouche, Florence Pasquier, Christophe Marzac, François Girodon, William Vainchenker, Mark Drummond, Claire Harrison, J. Ross Chapman, Isabelle Plo, Sten Eirik W. Jacobsen, Bethan Psaila, Supat Thongjuea, Iléana Antony-Debré, Adam J. Mead

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29 Citations (Scopus)

Abstract

Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 ‘multihit’ HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.

Original language	English
Pages (from-to)	1531-1541
Number of pages	11
Journal	Nature Genetics
Volume	55
Issue number	9
DOIs	https://doi.org/10.1038/s41588-023-01480-1
Publication status	Published - 1 Sept 2023

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Rodriguez-Meira, A., Norfo, R., Wen, S., Chédeville, A. L., Rahman, H., O’Sullivan, J., Wang, G., Louka, E., Kretzschmar, W. W., Paterson, A., Brierley, C., Martin, J. E., Demeule, C., Bashton, M., Sousos, N., Moralli, D., Subha Meem, L., Carrelha, J., Wu, B., ... Mead, A. J. (2023). Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution. Nature Genetics, 55(9), 1531-1541. https://doi.org/10.1038/s41588-023-01480-1

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title = "Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution",

abstract = "Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 {\textquoteleft}multihit{\textquoteright} HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.",

author = "Alba Rodriguez-Meira and Ruggiero Norfo and Sean Wen and Ch{\'e}deville, {Agathe L.} and Haseeb Rahman and Jennifer O{\textquoteright}Sullivan and Guanlin Wang and Eleni Louka and Kretzschmar, {Warren W.} and Aimee Paterson and Charlotte Brierley and Martin, {Jean Edouard} and Caroline Demeule and Matthew Bashton and Nikolaos Sousos and Daniela Moralli and {Subha Meem}, Lamia and Joana Carrelha and Bishan Wu and Angela Hamblin and Helene Guermouche and Florence Pasquier and Christophe Marzac and Fran{\c c}ois Girodon and William Vainchenker and Mark Drummond and Claire Harrison and Chapman, {J. Ross} and Isabelle Plo and Jacobsen, {Sten Eirik W.} and Bethan Psaila and Supat Thongjuea and Il{\'e}ana Antony-Debr{\'e} and Mead, {Adam J.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = sep,

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doi = "10.1038/s41588-023-01480-1",

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Rodriguez-Meira, A, Norfo, R, Wen, S, Chédeville, AL, Rahman, H, O’Sullivan, J, Wang, G, Louka, E, Kretzschmar, WW, Paterson, A, Brierley, C, Martin, JE, Demeule, C, Bashton, M, Sousos, N, Moralli, D, Subha Meem, L, Carrelha, J, Wu, B, Hamblin, A, Guermouche, H, Pasquier, F, Marzac, C, Girodon, F, Vainchenker, W, Drummond, M, Harrison, C, Chapman, JR, Plo, I, Jacobsen, SEW, Psaila, B, Thongjuea, S, Antony-Debré, I & Mead, AJ 2023, 'Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution', Nature Genetics, vol. 55, no. 9, pp. 1531-1541. https://doi.org/10.1038/s41588-023-01480-1

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T1 - Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution

AU - Rodriguez-Meira, Alba

AU - Norfo, Ruggiero

AU - Wen, Sean

AU - Chédeville, Agathe L.

AU - Rahman, Haseeb

AU - O’Sullivan, Jennifer

AU - Wang, Guanlin

AU - Louka, Eleni

AU - Kretzschmar, Warren W.

AU - Paterson, Aimee

AU - Brierley, Charlotte

AU - Martin, Jean Edouard

AU - Demeule, Caroline

AU - Bashton, Matthew

AU - Sousos, Nikolaos

AU - Moralli, Daniela

AU - Subha Meem, Lamia

AU - Carrelha, Joana

AU - Wu, Bishan

AU - Hamblin, Angela

AU - Guermouche, Helene

AU - Pasquier, Florence

AU - Marzac, Christophe

AU - Girodon, François

AU - Vainchenker, William

AU - Drummond, Mark

AU - Harrison, Claire

AU - Chapman, J. Ross

AU - Plo, Isabelle

AU - Jacobsen, Sten Eirik W.

AU - Psaila, Bethan

AU - Thongjuea, Supat

AU - Antony-Debré, Iléana

AU - Mead, Adam J.

PY - 2023/9/1

Y1 - 2023/9/1

N2 - Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 ‘multihit’ HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.

AB - Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 ‘multihit’ HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.

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U2 - 10.1038/s41588-023-01480-1

DO - 10.1038/s41588-023-01480-1

M3 - Article

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AN - SCOPUS:85169800659

SN - 1061-4036

VL - 55

SP - 1531

EP - 1541

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution

Abstract

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