TY - JOUR
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.
N1 - Funding information: We are grateful to patients and donors as without their generosity, this study would not have been possible. We also thank S. Knapper, clinical study teams and other investigators involved in supporting sample collection, and King’s Health Partners Biobank for providing access to samples. We thank Z. Ren, T. Denaes and H. Duparc for their help with mouse experiments and S.-A. Clark for help with sorting. We also thank C. Soblechero for the help with computational analysis. This work was funded by a Medical Research Council (MRC) Senior Clinical Fellowship (MR/L006340/1 to A.J.M.), CRUK Senior Cancer Research Fellowship (C42639/A26988 to A.J.M.), Cancer Research UK (CRUK) DPhil Prize Studentship (C5255/A20936 to A.R.-M.), Sir Henry Wellcome Postdoctoral Fellowship from the Wellcome Trust (222800/Z/21/Z to A.R.-M.), British Spanish Society Scholarship (to A.R.-M.), MRC Confidence in Concept/MLSTF Grant (MC_PC_19049 to A.R.-M. and A.J.M.), the MRC Molecular Haematology Unit core award (MC_UU_12009/5 to A.J.M. and S.E.W.J.), Emergence Cancéropôle Ile de France 2017 (to I.A.-D.), Association pour la Recherche contre le Cancer 2018 (to I.A.-D.), Gustave Roussy Siric-Socrate 2019 (to I.A.-D.), Institut National du Cancer INCA-PLBIO 2020 (to I.A.-D.) and La Ligue Nationale Contre le Cancer (Equipe labellisée 2019 and 2022 to I.P. and I.A.-D.). A.L.C. was supported by Paris University (MENRT grant), J.R.C. by a CRUK Senior Cancer Research Fellowship (RCCSCF-Nov21\100004) and S.E.W.J. by the Swedish Research Council, Torsten Söderberg Foundation and Knut and Alice Wallenberg Foundation. F.G. was supported by grants from the association ‘Chalon sur Saône-Tulipes contre le cancer’ and the Centre de Ressources Biologiques Ferdinand Cabanne. The authors would like to acknowledge the flow cytometry facility at the MRC Weatherall Institute of Molecular Medicine (WIMM), which is supported by the MRC Human Immunology Unit; MRC Molecular Haematology Unit (MC_UU_12009); National Institute for Health Research (NIHR), Oxford Biomedical Research Centre (BRC); Kay Kendall Leukemia Fund (KKL1057), John Fell Fund (131/030 and 101/517), the EPA fund (CF182 and CF170) and by the MRC WIMM Strategic Alliance awards (G0902418 and MC_UU_12025). The authors acknowledge the contributions of N. Ashley at the MRC Weatherall Institute of Molecular Medicine (WIMM) Single Cell Facility and MRC-funded Oxford Consortium for Single-Cell Biology (MR/M00919X/1). The authors would also like to acknowledge the contribution of the WIMM Sequencing Facility, supported by the MRC Human Immunology Unit and by the EPA fund (CF268), the Gustave Roussy flow cytometry platform and mouse facility. We also thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of the OmniExpress SNP array data. The results published here are in whole or part based upon data generated by the TCGA Research Network (https://www.cancer.gov/tcga) and the BeatAML team. The views expressed are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
PY - 2023/9/4
Y1 - 2023/9/4
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.
U2 - 10.1038/s41588-023-01480-1
DO - 10.1038/s41588-023-01480-1
M3 - Article
SN - 1061-4036
VL - 55
SP - 1531
EP - 1541
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -
