Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

Michael R. Green1,2, Shingo Kihira3, Chih Long Liu3, Ramesh V. Nair4,5, Raheleh Salari6, Andrew J. Gentles7,5, Jonathan M. Irish3, Henning Stehr8, Carolina Vicente‐Dueñas9,10, Isabel Romero-Camarero9,10, Isidro Sánchez‐García9,10, Sylvia K. Plevritis7,5, Daniel A. Arber11, Serafim Batzoglou6, Ronald Levy1,12,8, Ash A. Alizadeh1,12,8
1Center for Cancer Systems Biology
2Center for Cancer Systems Biology,; Division of Oncology,
3Division of Oncology
4Division of Oncology,; Division of Radiology,
5Division of Radiology
6Department of Computer Science, and
7Center for Cancer Systems Biology,; Division of Radiology,
8Stanford Cancer Institute, Department of Medicine, Stanford University, Stanford, CA 94305;
9Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Campus M. de Unamuno s/n, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Salamanca 37007, Spain;
10Institute of Biomedical Research of Salamanca, Salamanca 37007, Spain; and
11Department of Pathology, Stanford University, Stanford, CA 94305
12Center for Cancer Systems Biology,; Division of Oncology,; Stanford Cancer Institute, Department of Medicine, Stanford University, Stanford, CA 94305;

Tóm tắt

Significance Follicular lymphoma (FL) is a disease characterized by multiple relapses that are linked by a common progenitor bearing only a subset of the mutations found within the tumor that presents clinically. Inability to cure this disease may therefore be linked to the failure of current therapies to clear these early tumor-propagating clones. Here we further define the genetic hallmarks of this disease and model the steps in evolution through phylogenetic analysis of serial tumor biopsies. This identified CREBBP mutations as early events in genome evolution that are enriched within tumor cell progenitors and provided evidence that these mutations act by allowing immune evasion. This highlights CREBBP mutations as an attractive therapeutic target in FL and provides insight into their pathogenic mechanism.

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