Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

Ferran Nadeu; Romina Royo; Ramon Massoni-Badosa; Heribert Playa-Albinyana; Beatriz Garcia-Torre; Martí Duran-Ferrer; Kevin J. Dawson; Marta Kulis; Ander Diaz-Navarro; Neus Villamor; Juan L. Melero; Vicente Chapaprieta; Ana Dueso-Barroso; Julio Delgado; Riccardo Moia; Sara Ruiz-Gil; Domenica Marchese; Ariadna Giró; Núria Verdaguer-Dot; Mónica Romo; Guillem Clot; Maria Rozman; Gerard Frigola; Alfredo Rivas-Delgado; Tycho Baumann; Miguel Alcoceba; Marcos González; Fina Climent; Pau Abrisqueta; Josep Castellví; Francesc Bosch; Marta Aymerich; Anna Enjuanes; Sílvia Ruiz-Gaspà; Armando López-Guillermo; Pedro Jares; Sílvia Beà; Salvador Capella-Gutierrez; Josep Ll Gelpí; Núria López-Bigas; David Torrents; Peter J. Campbell; Ivo Gut; Davide Rossi; Gianluca Gaidano; Xose S. Puente; Pablo M. Garcia-Roves; Dolors Colomer; Holger Heyn; Francesco Maura; José I. Martín-Subero; Elías Campo

doi:10.1038/s41591-022-01927-8

Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

Ferran Nadeu, Romina Royo, Ramon Massoni-Badosa, Heribert Playa-Albinyana, Beatriz Garcia-Torre, Martí Duran-Ferrer, Kevin J. Dawson, Marta Kulis, Ander Diaz-Navarro, Neus Villamor, Juan L. Melero, Vicente Chapaprieta, Ana Dueso-Barroso, Julio Delgado, Riccardo Moia, Sara Ruiz-Gil, Domenica Marchese, Ariadna Giró, Núria Verdaguer-Dot, Mónica RomoGuillem Clot, Maria Rozman, Gerard Frigola, Alfredo Rivas-Delgado, Tycho Baumann, Miguel Alcoceba, Marcos González, Fina Climent, Pau Abrisqueta, Josep Castellví, Francesc Bosch, Marta Aymerich, Anna Enjuanes, Sílvia Ruiz-Gaspà, Armando López-Guillermo, Pedro Jares, Sílvia Beà, Salvador Capella-Gutierrez, Josep Ll Gelpí, Núria López-Bigas, David Torrents, Peter J. Campbell, Ivo Gut, Davide Rossi, Gianluca Gaidano, Xose S. Puente, Pablo M. Garcia-Roves, Dolors Colomer, Holger Heyn, Francesco Maura, José I. Martín-Subero, Elías Campo

Dipartimento di Medicina Traslazionale

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

Abstract

Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)^high–B cell receptor (BCR)^low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.

Lingua originale	Inglese
pagine (da-a)	1662-1671
Numero di pagine	10
Rivista	Nature Medicine
Volume	28
Numero di pubblicazione	8
DOI	https://doi.org/10.1038/s41591-022-01927-8
Stato di pubblicazione	Pubblicato - ago 2022

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Nadeu, F., Royo, R., Massoni-Badosa, R., Playa-Albinyana, H., Garcia-Torre, B., Duran-Ferrer, M., Dawson, K. J., Kulis, M., Diaz-Navarro, A., Villamor, N., Melero, J. L., Chapaprieta, V., Dueso-Barroso, A., Delgado, J., Moia, R., Ruiz-Gil, S., Marchese, D., Giró, A., Verdaguer-Dot, N., ... Campo, E. (2022). Detection of early seeding of Richter transformation in chronic lymphocytic leukemia. Nature Medicine, 28(8), 1662-1671. https://doi.org/10.1038/s41591-022-01927-8

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title = "Detection of early seeding of Richter transformation in chronic lymphocytic leukemia",

abstract = "Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high–B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.",

author = "Ferran Nadeu and Romina Royo and Ramon Massoni-Badosa and Heribert Playa-Albinyana and Beatriz Garcia-Torre and Mart{\'i} Duran-Ferrer and Dawson, {Kevin J.} and Marta Kulis and Ander Diaz-Navarro and Neus Villamor and Melero, {Juan L.} and Vicente Chapaprieta and Ana Dueso-Barroso and Julio Delgado and Riccardo Moia and Sara Ruiz-Gil and Domenica Marchese and Ariadna Gir{\'o} and N{\'u}ria Verdaguer-Dot and M{\'o}nica Romo and Guillem Clot and Maria Rozman and Gerard Frigola and Alfredo Rivas-Delgado and Tycho Baumann and Miguel Alcoceba and Marcos Gonz{\'a}lez and Fina Climent and Pau Abrisqueta and Josep Castellv{\'i} and Francesc Bosch and Marta Aymerich and Anna Enjuanes and S{\'i}lvia Ruiz-Gasp{\`a} and Armando L{\'o}pez-Guillermo and Pedro Jares and S{\'i}lvia Be{\`a} and Salvador Capella-Gutierrez and Gelp{\'i}, {Josep Ll} and N{\'u}ria L{\'o}pez-Bigas and David Torrents and Campbell, {Peter J.} and Ivo Gut and Davide Rossi and Gianluca Gaidano and Puente, {Xose S.} and Garcia-Roves, {Pablo M.} and Dolors Colomer and Holger Heyn and Francesco Maura and Mart{\'i}n-Subero, {Jos{\'e} I.} and El{\'i}as Campo",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = aug,

doi = "10.1038/s41591-022-01927-8",

language = "English",

volume = "28",

pages = "1662--1671",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "8",

}

Nadeu, F, Royo, R, Massoni-Badosa, R, Playa-Albinyana, H, Garcia-Torre, B, Duran-Ferrer, M, Dawson, KJ, Kulis, M, Diaz-Navarro, A, Villamor, N, Melero, JL, Chapaprieta, V, Dueso-Barroso, A, Delgado, J, Moia, R, Ruiz-Gil, S, Marchese, D, Giró, A, Verdaguer-Dot, N, Romo, M, Clot, G, Rozman, M, Frigola, G, Rivas-Delgado, A, Baumann, T, Alcoceba, M, González, M, Climent, F, Abrisqueta, P, Castellví, J, Bosch, F, Aymerich, M, Enjuanes, A, Ruiz-Gaspà, S, López-Guillermo, A, Jares, P, Beà, S, Capella-Gutierrez, S, Gelpí, JL, López-Bigas, N, Torrents, D, Campbell, PJ, Gut, I, Rossi, D, Gaidano, G, Puente, XS, Garcia-Roves, PM, Colomer, D, Heyn, H, Maura, F, Martín-Subero, JI & Campo, E 2022, 'Detection of early seeding of Richter transformation in chronic lymphocytic leukemia', Nature Medicine, vol. 28, n. 8, pagg. 1662-1671. https://doi.org/10.1038/s41591-022-01927-8

TY - JOUR

T1 - Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

AU - Nadeu, Ferran

AU - Royo, Romina

AU - Massoni-Badosa, Ramon

AU - Playa-Albinyana, Heribert

AU - Garcia-Torre, Beatriz

AU - Duran-Ferrer, Martí

AU - Dawson, Kevin J.

AU - Kulis, Marta

AU - Diaz-Navarro, Ander

AU - Villamor, Neus

AU - Melero, Juan L.

AU - Chapaprieta, Vicente

AU - Dueso-Barroso, Ana

AU - Delgado, Julio

AU - Moia, Riccardo

AU - Ruiz-Gil, Sara

AU - Marchese, Domenica

AU - Giró, Ariadna

AU - Verdaguer-Dot, Núria

AU - Romo, Mónica

AU - Clot, Guillem

AU - Rozman, Maria

AU - Frigola, Gerard

AU - Rivas-Delgado, Alfredo

AU - Baumann, Tycho

AU - Alcoceba, Miguel

AU - González, Marcos

AU - Climent, Fina

AU - Abrisqueta, Pau

AU - Castellví, Josep

AU - Bosch, Francesc

AU - Aymerich, Marta

AU - Enjuanes, Anna

AU - Ruiz-Gaspà, Sílvia

AU - López-Guillermo, Armando

AU - Jares, Pedro

AU - Beà, Sílvia

AU - Capella-Gutierrez, Salvador

AU - Gelpí, Josep Ll

AU - López-Bigas, Núria

AU - Torrents, David

AU - Campbell, Peter J.

AU - Gut, Ivo

AU - Rossi, Davide

AU - Gaidano, Gianluca

AU - Puente, Xose S.

AU - Garcia-Roves, Pablo M.

AU - Colomer, Dolors

AU - Heyn, Holger

AU - Maura, Francesco

AU - Martín-Subero, José I.

AU - Campo, Elías

PY - 2022/8

Y1 - 2022/8

N2 - Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high–B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.

AB - Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high–B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.

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U2 - 10.1038/s41591-022-01927-8

DO - 10.1038/s41591-022-01927-8

M3 - Article

SN - 1078-8956

VL - 28

SP - 1662

EP - 1671

JO - Nature Medicine

JF - Nature Medicine

IS - 8

ER -

Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

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