细胞信号通路 Diffuse Large B Cell Lymphoma

S h a r e d G C B - & A B C -D L B C L

CELL OF ORIGIN

Naive B cell

Ag

CD79A/B

LYN

PKC β

MAPK/ERK PI3K/AKT

CARD11

BCL10

MALT1

IRF4

MyD88

K4

H3

H3

K27

K27

Transcriptional activators

EZH2SUZ12

Transcriptional repressors

BCL6BCL6-i CD40

CD40L TLR/IL-1R

BTK-i

11%

20-40%

32%

4%

21%25-32%

25%30%21%

30-37%

10%

32%22%

24-30%

11%

10%

29%

NF-κB

IRF4

BCL6 translocation; more frequent in ABC-DLBCL

GCB-DLBCL

ABC-DLBCL

BCL6 translocation

*Based on analysis of 12 cases only

MEF2B BCL6 gene

BCL6 protein

DARK ZONE

Germinal Center

GCB-DLBCL ABC-DLBCL

PMBCL

LIGHT ZONE Centroblast HLA-I loss relieves inhibition on NK

Non-self antigen activates CTL

Centrocyte

T cell

FDC

Plasmablast

Plasma cell

Memory B cell

Thymus

Thymic B cell

IMMUNE ESCAPE

DEREGULATED BCL6 ACTIVITY

CONSTITUTIVE BCR AND NF-κB SIGNALING

ABERRANT HISTONE/

CHROMATIN MODIFICATIONS

G C B -D L B C L

M u t a t i o n s

Loss of function Gain of function D e l e t i o n s

T r a n s l o c a t i o n s

A m p l i c a t i o n s

C N g a i n s

A B C -D L B C L

P M B C L

3232-382921

20-4011820

% of DLBCL

% of subtype

Altered histone/

chromatin modi?cations CREBBP/EP300

MLL2/MLL3Proliferation/Apoptosis

BCL2MYC

miR-17~92Other EZH2

BCL6 BSE1 sites

2p16.1Immune escape

B2M CD58Deregulated BCL6 activity

BCL6MEF2B

34-45

106-12.5221516

30

30-372110

30-454536

3630-4538

33*

25-32

13

24-3026

Signaling TNFRSF14

GNA13SGK1PTEN Constitutive

NF-κB/BCR activity

TNFAIP3MYD88CD79A/B CARD11

Terminal

differentiation block

PRDM1/BLIMP1

Apoptosis

BCL2Other SPIB

JAK/STAT activation

JAK2/JMJD2C

SOCS1STAT6

Cell cycle checkpoint CDKN2A/B

Constitutive NF-κB activity

TNFAIP3Immune escape

PDL1/PDL2

CIITA Deregulated BCL6 activity

BCL6

1311136-11Other FOXO1TP53

MALT1-i

T cell

CD2Non-self Ag

TCR

CD58

NK

CTL

DNA damage response (p53, ATR)Cell cycle arrest (p21)

B cell activation (CD80)Programmed cell death (BCL2)Plasma cell differentiation (BLIMP1)

NK CTL

NF-κB

NF-κB-i

HDAC-i

EZH2-i Lenalidomide JAK/STAT Interferon p38/MAPK

Ag

BCR SYK BTK

HLA-I

Normal

B cell DLBCL

FBXO11A20

PRDM1

CBP/EP300

K4 methylation K27 methylation K27 acetylation

Loss of function genetic lesions

Gain of function genetic lesions

CREBBP

EP300MLL2MLL3Columbia University, New York, NY 10032, USA

See online version for legend and references.

132 Cancer Cell 25, January 13, 2014 ?2014 Elsevier Inc. DOI 10.1016/https://www.360docs.net/doc/be1235615.html,r.2013.12.012

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 dysregu-lated 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-k B 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-k B 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-k B transcription factor represents a hallmark of ABC-DLBCL. The underlying causes are heterogeneous and include gain-of-function muta-tions 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-k B negative regulator TNFAIP3/A20. While specific NF-k B 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-k B 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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132.e1Cancer Cell 25, January 13, 2014 ?2014 Elsevier Inc. DOI 10.1016/https://www.360docs.net/doc/be1235615.html,r.2013.12.012