Clinical and biological subtypes of b-cell lymphoma revealed by microenvironmental signatures

Nikita Kotlov; Alexander Bagaev; Maria V. Revuelta; Jude M. Phillip; Maria Teresa Cacciapuoti; Zoya Antysheva; Viktor Svekolkin; Ekaterina Tikhonova; Natalia Miheecheva; Natalia Kuzkina; Grigorii Nos; Fabrizio Tabbo; Felix Frenkel; Paola Ghione; Maria Tsiper; Nava Almog; Nathan Fowler; Ari M. Melnick; John P. Leonard; Giorgio Inghirami; Leandro Cerchietti

doi:10.1158/2159-8290.CD-20-0839

Clinical and biological subtypes of b-cell lymphoma revealed by microenvironmental signatures

Nikita Kotlov, Alexander Bagaev, Maria V. Revuelta, Jude M. Phillip, Maria Teresa Cacciapuoti, Zoya Antysheva, Viktor Svekolkin, Ekaterina Tikhonova, Natalia Miheecheva, Natalia Kuzkina, Grigorii Nos, Fabrizio Tabbo, Felix Frenkel, Paola Ghione, Maria Tsiper, Nava Almog, Nathan Fowler, Ari M. Melnick, John P. Leonard, Giorgio InghiramiLeandro Cerchietti

Research output: Contribution to journal › Article › peer-review

102 Scopus citations

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogene-ous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment. Significance: In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.

Original language	English (US)
Pages (from-to)	1468-1489
Number of pages	22
Journal	Cancer discovery
Volume	11
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-20-0839
State	Published - 2021
Externally published	Yes

ASJC Scopus subject areas

Oncology

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Kotlov, N., Bagaev, A., Revuelta, M. V., Phillip, J. M., Cacciapuoti, M. T., Antysheva, Z., Svekolkin, V., Tikhonova, E., Miheecheva, N., Kuzkina, N., Nos, G., Tabbo, F., Frenkel, F., Ghione, P., Tsiper, M., Almog, N., Fowler, N., Melnick, A. M., Leonard, J. P., ... Cerchietti, L. (2021). Clinical and biological subtypes of b-cell lymphoma revealed by microenvironmental signatures. Cancer discovery, 11(6), 1468-1489. https://doi.org/10.1158/2159-8290.CD-20-0839

Kotlov, N, Bagaev, A, Revuelta, MV, Phillip, JM, Cacciapuoti, MT, Antysheva, Z, Svekolkin, V, Tikhonova, E, Miheecheva, N, Kuzkina, N, Nos, G, Tabbo, F, Frenkel, F, Ghione, P, Tsiper, M, Almog, N, Fowler, N, Melnick, AM, Leonard, JP, Inghirami, G & Cerchietti, L 2021, 'Clinical and biological subtypes of b-cell lymphoma revealed by microenvironmental signatures', Cancer discovery, vol. 11, no. 6, pp. 1468-1489. https://doi.org/10.1158/2159-8290.CD-20-0839

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title = "Clinical and biological subtypes of b-cell lymphoma revealed by microenvironmental signatures",

abstract = "Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogene-ous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment. Significance: In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.",

author = "Nikita Kotlov and Alexander Bagaev and Revuelta, {Maria V.} and Phillip, {Jude M.} and Cacciapuoti, {Maria Teresa} and Zoya Antysheva and Viktor Svekolkin and Ekaterina Tikhonova and Natalia Miheecheva and Natalia Kuzkina and Grigorii Nos and Fabrizio Tabbo and Felix Frenkel and Paola Ghione and Maria Tsiper and Nava Almog and Nathan Fowler and Melnick, {Ari M.} and Leonard, {John P.} and Giorgio Inghirami and Leandro Cerchietti",

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doi = "10.1158/2159-8290.CD-20-0839",

language = "English (US)",

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AU - Kotlov, Nikita

AU - Bagaev, Alexander

AU - Revuelta, Maria V.

AU - Phillip, Jude M.

AU - Cacciapuoti, Maria Teresa

AU - Antysheva, Zoya

AU - Svekolkin, Viktor

AU - Tikhonova, Ekaterina

AU - Miheecheva, Natalia

AU - Kuzkina, Natalia

AU - Nos, Grigorii

AU - Tabbo, Fabrizio

AU - Frenkel, Felix

AU - Ghione, Paola

AU - Tsiper, Maria

AU - Almog, Nava

AU - Fowler, Nathan

AU - Melnick, Ari M.

AU - Leonard, John P.

AU - Inghirami, Giorgio

AU - Cerchietti, Leandro

PY - 2021

Y1 - 2021

N2 - Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogene-ous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment. Significance: In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.

AB - Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogene-ous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment. Significance: In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.

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Clinical and biological subtypes of b-cell lymphoma revealed by microenvironmental signatures

Abstract

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