Snapshot: Diffuse Large B Cell Lymphoma

1 aur 3 04©04Esve n. DOI 10.1016/j.ccr.2013.12.012 Cancer Cell 25,January 13, 2014©2014 Elsevier Inc. 132 4 Laura Pasqualucci Cell B Lymphoma Large Diffuse SnapShot: Columbia University, NewYork, NY10032,USA Department ofMicrobiology andImmunology, Institute forCancerGenetics, PMBCL ABC-DLBCL GCB-DLBCL Shared GCB- & ABC-DLBCL JAK/STAT activation differentiation block NF-κB/BCR activity BCL6 BSE1sites Altered histone/ Immune escape Immune escape PRDM1/BLIMP1 CREBBP/EP300 NF-κB activity JAK2/JMJD2C modiﬁcations Loss offunction Gain offunction BCL6 activity BCL6 activity Proliferation/ Deregulated Deregulated Constitutive Constitutive MLL2/MLL3 checkpoint PDL1/PDL2 chromatin CDKN2A/B miR-17~92 TNFRSF14 Apoptosis Apoptosis Cell cycle Signaling CD79A/B Terminal TNFAIP3 TNFAIP3 CARD11 SOCS1 MYD88 MEF2B GNA13 FOXO1 2p16.1 STAT6 Other Other Other SGK1 PTEN CD58 BCL2 BCL6 BCL2 BCL6 EZH2 CIITA TP53 SPIB MYC B2M 1,2,5 *Based onanalysisof12cases only andRiccardo Dalla-Favera subtype 6-12.5 DLBCL 24-30 25-32 30-45 30-45 30-37 34-45 20-40 32-38 % of % of 6-11 33* 26 13 38 36 36 45 10 21 30 16 15 22 10 20 11 21 29 32 13 11 13 8

Mutations 2 Deletions Department ofPathologyandCellBiology, Translocations Ampli cations CN gains CHROMATIN MODIFICATIONS ABERRANT HISTONE/ CELL OFORIGIN IMMUNE ESCAPE EZH2-i NK NK GCB-DLBCL Naive B cell Ag 4mtyainK7mtyainK27 acetylation K27 methylation K4 methylation HLA-I lossrelieves inhibition onNK 5 Herbert IrvingComprehensive CancerCenter, H3 1,2,3,4,5 CD2 H3 K4 22% EZH2 K27 CD58 21% SUZ12 Centroblast K27 Normal DLBCL C-LC ABC-DLBCL GCB-DLBCL B cell DARK ZONE Transcriptional repressors Non-self antigen activates CTL Transcriptional HLA-I activators Non-self 29% Germinal Center MLL2 32% Centrocyte Ag MLL3 TCR 10% CREBBP 3 24-30% T cell Department ofGenetics, HDAC-i EP300 LIGHT ZONE FDC 11% CTL CTL Plasmablast (p53, ATR) response CD79A/B BCL6 ACTIVITY DEREGULATED AND NF-κ CONSTITUTIVE BCR damage DNA 21% Lenalidomide 30% MALT1-i Ag MAPK/ERK BCL6-i LYN PI3K/AKT arrest genetic lesions Loss offunction cycle (p21) Cell A20 B SIGNALING BO1CBP/EP300 FBXO11 FBXO11 BCR SYK Plasma cell Memory 4% B cell MEF2B activation BCL6 protein (CD80) 11% B cell BCL6 gene PKCβ BTK-i BTK NF- MALT1 C6PRDM1 BCL6 IRF4 BCL10 κ CBP/EP300 NF-κB B 25% CARD11 IRF4 Programmed cell death (BCL2) 32% legend and references. 20-40% BCL6 translocation genetic lesions Gain offunction See online version for for version online See MyD88 CD40 NF-κ CD40L PMBCL Thymus 10% Thymic B cell PRDM1 T cell 25-32% ABC-DLBCL more frequent in BCL6 translocation; B-i ABC-DLBCL differentiation Plasma cell 30-37% TLR/IL-1R p38/MAPK (BLIMP1) JAK/STAT Interferon SnapShot: Diffuse Large B Cell Lymphoma Laura Pasqualucci1,2,5 and Riccardo Dalla-Favera1,2,3,4,5 1Institute for Cancer Genetics, 2Department of Pathology and Cell Biology, 3Department of Genetics, 4Department of Microbiology and Immunology, 5Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA

Diffuse large B cell lymphoma (DLBCL) is the most prevalent non-Hodgkin lymphoma (NHL) in adulthood, comprising 30%–40% of all new diagnoses. This aggressive disease can arise de novo or, less frequently, from the clinical evolution of various indolent B cell malignancies. While durable remissions can be achieved in a substantial proportion of cases by combined chemoimmunotherapy, over 30% of patients will not respond to currently available regimens or will relapse with resistant disease. One explanation for such incomplete therapeutic success is the considerable heterogeneity of this tumor. DLBCL comprises multiple molecular subgroups, which can be recognized by their gene expression profiles and reflect either the stage in B cell development from which the disease originates or the activity of different biological programs, including metabolic dysregulation. DLBCL subgroups differ in the oncogenic pathways that drive them and in their response to treatment. Thus, the recognition of dysregulated genes/programs that are critical to the survival of the lymphoma cells is central to the development of rationally targeted therapeutic approaches for DLBCL.

Cell of Origin Analogous to most B-NHL, DLBCL derives from a mature B cell that has experienced the germinal center (GC) reaction. DLBCLs have been divided into three subgroups based on putative cells of origin. GC B cell-like (GCB)-DLBCL exhibits a transcriptional profile that resembles that of GC B cells, including having elevated expression of BCL6 and the presence of hypermutated immunoglobulin genes with ongoing somatic hypermutation (SHM). Activated B cell-like (ABC)-DLBCL shows several features of BCR-activated B cells entering plasmablastic differentiation; these tumors downregulate the GC-specific program, concomitant with activation of NF-kB and BCR signaling pathways, and upregulate genes required for plasma cell differentiation (e.g., IRF4). Consistent with their late GC origin, ABC-DLBCLs do not show evidence of ongoing SHM. Primary medi- astinal B cell lymphoma (PMBCL) is postulated to arise from a post-GC thymic B cell in the mediastinum and shares histological, molecular, and clinical features with nodular sclerosis Hodgkin lymphoma, including a robust immune/inflammatory cell infiltrate, a distinctive cytokine profile, and constitutive NF-kB activation. An additional 15%–30% of DLBCL cases remain unclassified. Stratification of DLBCL patients according to the cell-of-origin classification was shown to have prognostic significance, with GCB-DLBCL displaying a better overall survival compared to ABC-DLBCL.

Genetic Alterations Compared to other B cell malignancies, DLBCL shows a significantly higher degree of genomic complexity, typically harboring between 50 and >100 lesions per case, with high variability across patients. These figures, which include point mutations, copy number aberrations, and chromosomal translocations, likely represent an underestimate because sequencing studies performed so far have not interrogated noncoding portions of the genome. Recent genomic analysis of DLBCL revealed a number of previously unrecognized genes/pathways that are dysregulated by genetic lesions and presumably play central roles in tumor initiation and maintenance. Some of these lesions can be observed in both GCB and ABC subtypes of DLBCL, while others are preferentially associated with individual DLBCL subtypes, suggesting their potential for diagnostic and therapeutic stratification. The following paragraphs focus on the most frequent and well-character- ized alterations (see the table for a comprehensive list).

Alterations Shared Across Subtypes Inactivating mutations and deletions of the histone acetyltransferases CREBBP/EP300 and the histone methyltransferase MLL2 emerged as the most common genetic lesions in DLBCL, where they may favor tumor development by reprogramming the cancer epigenome. The prevalence of these lesions has therapeutic implications given the potential of histone deacetylase inhibitors to restore physiologic acetylation levels. A multitude of genetic lesions result in deregulation of BCL6 activity, either directly (chromosomal translocations or mutations abrogating its promoter regulatory sequences) or indirectly, by enhancing the activity of its positive regulator MEF2B, preventing acetylation-mediated inactivation of its function (CREBBP/EP300 mutations/ deletions), or abrogating mechanisms controlling protein degradation (FBXO11 mutations/deletions). Notably, pharmacologic inhibition of BCL6 is lethal to most DLBCL. DLBCL cells acquire the ability to escape immune surveillance, including CTL-mediated cytotoxicity (through genetic loss of B2M or HLA-I genes) and natural killer cell- mediated death (through loss of the gene encoding the CD58 ligand). In PMBCL, reduced tumor cell immunogenicity is achieved by disruption of the MHC-II transactivator CIITA and amplification of PDL1 and/or PDL2, genes encoding for immunomodulatory proteins. Most DLBCLs harbor mutations in multiple genes as the result of an aberrant function of the physiologic SHM mechanism. While the causes of this phenomenon are unknown, its widespread activity may have powerful consequences by promoting genomic instability, favoring DNA breaks/chromosomal translocations, and deregulating oncogenes or tumor suppressor genes.

Subtype-Associated Alterations Translocations resulting in deregulated MYC and BCL2 and gain-of-function mutations in the H3K27 methyltransferase EZH2 are exquisitely restricted to GCB-DLBCL. Also frequent for this subtype, but of unclear functional role, are truncating mutations in TNFRSF14, encoding a TNF-receptor superfamily member, and mutations of GNA13, encoding a G protein involved in Rho GTPase signaling. Importantly, EZH2 inhibitors showed specific activity against EZH2 mutated tumors in preclinical studies. Constitutive activation of the NF-kB transcription factor represents a hallmark of ABC-DLBCL. The underlying causes are heterogeneous and include gain-of-function mutations in several signal transduction components of the BCR (CD79B and CARD11) and Toll-like receptor (MyD88) signaling pathway or loss-of-function mutations in the NF-kB negative regulator TNFAIP3/A20. While specific NF-kB inhibitors are under development, kinase inhibitors that interfere with BCR signaling (e.g., BTK inhibitors) are emerging as a new treatment paradigm for ABC-DLBCL. Impaired plasma cell differentiation is another major transformation mechanism in this subtype, caused by mutually exclusive lesions deregulating BCL6 and inactivating PRDM1/BLIMP1. In addition to abnormalities leading to constitutive NF-kB responses, several lesions converge on the JAK-STAT signaling pathway preferentially in PMBCL, suggesting a pathogenic role. Moreover, amplification of JAK2 and JMJD2C, encoding for a H3K9 demethylase, may favor epigenetic dysregulation and alter the transcription of multiple genes, including MYC.

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