Contents
Preface
List of contributing authors
1. Classification of lymphomas – past, present and future
1.1 Classification – what is it good for?
1.2 The history of lymphoma classification
1.2.1 19th century: Tumors of lymphoid cells and their relation to leukemia
1.2.2 20th century: Description of individual diseases and historical lymphoma classifications
1.2.3 The second half of the 20th century: Modern lymphoma classifications, controversy and consensus
1.3 The principles of the current WHO classification
1.4 Future lymphoma classification – towards new hierarchical classification principles?
2. Mature B-cell development and the germinal center reaction
2.1 Introduction
2.2 The peripheral B-cell repertoire
2.3 The germinal center reaction
2.3.1 Initiation of the GC reaction
2.3.2 GC formation and establishment of the mature GC
2.3.3 Somatic hypermutation
2.3.4 B cell movementswithin the zonal structure of the GC
2.3.5 Selection of high-affinity GC B cells
2.3.6 Class switch recombination
2.3.7 GC maintenance
2.3.8 Termination of the GC reaction and post-GC B-cell differentiation
2.4 Concluding remarks
3. T-cell development
3.1 Introduction
3.2 Overview
3.3 αβT
-cell repertoire
3.3.1 Antigen presentation and MHC molecules
3.3.2 Peripheral αβT
CR repertoires
3.4 The T-cell receptor
3.4.1 The variable chains of the T-cell receptor
3.4.2 The order and regulation of V(D)J recombination
3.4.3 Molecularmechanism of V(D)J recombination
3.4.4 Tumorigenic potential of TCR recombination
3.5 Thymus and early T-cell development
3.5.1 The thymus
3.5.2 Early T-cell development in the thymus
3.5.3 Positive selection
3.5.4 CD4 vs CD8 lineage commitment
3.5.5 Negative selection and exit from the thymus
3.6 TCR signaling – T-cell activation
3.6.1 TCR signaling complex
3.6.2 Activation and survival of naive T cells
3.6.3 Activated T-cell differentiation
3.6.4 Shutting down activated T cells
3.7 Concluding remarks
4. Mantle cell lymphoma
4.1 Introduction
4.2 Molecular pathogenesis ofMCL
4.2.1 Overexpression of cyclin D1 and cell cycle dysregulation
4.2.2 Additional genetic aberrations and deregulated signaling pathways
4.3 Clinical implications
4.4 BCR signaling inhibitors
4.5 PI3K/mTOR inhibitors
4.6 BCL2 inhibitors
4.7 Proteasome inhibitors
4.8 Concluding remarks
5. Follicular lymphoma
5.1 Introduction
5.2 Histology and grading
5.3 Transformed follicular lymphoma
5.4 Early steps of FL development: Initial genetic hit t(14;18)
5.5 Cell of origin
5.6 t(14;18) insufficient for lymphoma development
5.7 Intermediate steps in FL development
5.8 Existence of a progenitor clone
5.9 Molecular genetics of FL
5.9.1 Copy number alterations and copy neutral loss of heterozygosity
5.9.2 Genetic aberrations affecting key biological and signaling pathways
5.9.3 Alterations in epigenetic regulators
5.9.4 Alterations in immune modulators
5.9.5 Alterations affecting NF-?B signaling
5.9.6 Alterations affecting JAK-STAT signaling
5.9.7 Alterations affecting genes involved in cell proliferation and cell cycle regulation
5.9.8 Alterations in miscellaneous genes
5.10 Disease progression, transformation and clonal evolution
5.11 Other FL variants: Pediatric and t(14;18)-negative follicular lymphoma
5.12 Impact of the tumormicroenvironment
5.13 Susceptibility loci for FL
5.14 Concluding remarks
6. Genetics and molecular pathogenesis of marginal zone lymphoma
6.1 Introduction
6.2 Extranodalmarginal zone lymphoma of mucosa-associated lymphoid tissue
6.2.1 Etiology of MALT lymphoma
6.2.2 Role of immunological stimulation in the pathogenesis of MALT lymphoma
6.2.3 Genetic abnormalities in MALT lymphoma
6.2.4 Oncogenic cooperation between genetic abnormalities and antigenic stimulation
6.3 Splenic marginal zone lymphoma
6.3.1 Etiology of SMZL
6.3.2 Role of antigenic drive in pathogenesis of SMZL
6.3.3 Genetic abnormalities in SMZL
6.3.4 Oncogenic cooperation between genetic changes and antigenic stimulation
6.4 Concluding remarks
7. Burkitt lymphoma
7.1 Introduction
7.2 Cellular origin of Burkitt lymphoma
7.3 Genetic lesions involved in BL pathogenesis
7.3.1 Chromosomal translocations involving the c-MYC proto-oncogene
7.3.2 Mutations in TCF3 and ID3, and activation of PI3K signaling
7.3.3 Additional recurrent genetic lesions
7.4 Mouse models of Burkitt lymphoma
7.5 Conclusions and perspectives
8. Diffuse large B-cell lymphoma
8.1 Introduction
8.2 Cell of origin and classification
8.2.1 The “cell-of-origin” (COO) classification
8.2.2 The “comprehensive-consensus-cluster” (CCC) classification
8.3 Mechanisms of genetic lesion in DLBCL
8.3.1 Chromosomal translocations
8.3.2 Aberrant somatic hypermutation
8.4 The genetic landscape of DLBCL
8.5 Dysregulated pathways in DLBCL
8.5.1 Programs dysregulated in both GCB-DLBCL and ABC-DLBCL
8.5.2 Genetic lesions associated with GCB-DLBCL
8.5.3 Genetic lesions associated with ABC-DLBCL
8.5.4 Genetic lesions associated with histologic transformation of FL and CLL
8.6 Double-hit DLBCL
8.7 Concluding remarks
9. The biology of primary mediastinal large B-cell lymphoma
9.1 Introduction
9.2 Cell of origin and gene expression profiling
9.3 Molecular hallmarks of PMBCL
9.3.1 The mutational landscape of primary mediastinal large B-cell lymphoma
9.3.2 JAK-STAT pathway signaling
9.3.3 NF-?B signaling
9.3.4 Acquired immune privilege
9.3.5 Epigenetic changes
9.3.6 Biomarkers and therapeutic considerations
9.4 Concluding remarks
10. Molecular pathogenesis of primary central nervous system lymphoma
10.1 Introduction
10.2 Etiology
10.3 Clinical features and pathogenesis
10.4 Molecular pathogenesis of PCNSL
10.5 Role of the tumormicroenvironment in PCNSL
10.6 Concluding remarks
11. Chronic lymphocytic leukemia
11.1 Introduction
11.2 Clinical background
11.3 B-cell receptor signaling pathway
11.4 Notch signaling pathway
11.5 Other signaling pathways
11.6 Splicing
11.7 Apoptotic and cell cycle checkpoints
11.8 MYC network
11.9 Telomere function
11.10 Clonal architecture and evolution of CLL
11.11 Inherited susceptibility of CLL
11.12 Concluding remarks
12. Waldenström’s macroglobulinemia
12.1 Introduction
12.2 Epidemiology and patient characteristics
12.3 Nature of the WM clone
12.4 Chromosomal abnormalities inWM
12.5 MYD88 somatic mutations
12.6 CXCR4 somaticmutations
12.7 Other recurrent mutations
12.8 Microenvironmental interactions in WM
12.9 Concluding remarks
13. Molecular pathogenesis of multiplemyeloma
13.1 Introduction
13.2 Clinical stages of plasma cell neoplasms: a new definition of multiple myeloma
13.3 Chromosome translocations of the immunoglobulin genes are present in half of patients with MGUS and MM
13.4 Three groups of primary IgH translocations in ~ 40% of MM
13.5 Hyperdiploidy with multiple trisomies is another primary genetic event
13.6 Universal dysregulation of a cyclin D/RB axis in MM
13.7 Secondary genetic events associated with progression of MGUS to MM
13.7.1 MYC
13.7.2 Deletion 13
13.7.3 RAS pathway
13.8 High-risk MM is associated with subclonal tumor heterogeneity
13.9 Concluding remarks and future directions
14. Biology of Hodgkin’s lymphoma
14.1 Introduction
14.2 The cellular origin of the tumor cells in HL
14.3 Relationship of Hodgkin cells to Reed–Sternberg cells
14.4 The lost B-cell identity of HRS cells
14.5 Genetic lesions
14.6 Role of EBV in HL pathogenesis
14.7 Deregulated signaling pathways and transcription factors
14.8 Microenvironmental interactions
14.9 Lessons learnt from composite lymphomas
14.10 HL cell lines
15. Anaplastic large cell lymphoma
15.1 Introduction
15.2 Anaplastic large cell lymphoma, ALK-positive (ALK+ ALCL)
15.2.1 Clinical features
15.2.2 Morphology
15.2.3 Immunohistochemical markers
15.2.4 Patterns of ALK protein expression in ALK+ ALCL
15.2.5 Differential diagnosis
15.2.6 Genetic abnormalities and molecular pathogenesis of ALK+ ALCL
15.2.7 Prognostic factors and therapy
15.3 Anaplastic large cell lymphoma, ALK-negative (ALK- ALCL)
15.3.1 Epidemiology
15.3.2 Clinical features
15.3.3 Morphology and phenotype
15.3.4 Molecular studies
15.3.5 Prognosis
15.4 Primary cutaneous ALCL
15.5 Breast-implant ALCL
16. Molecular pathogenesis of malignant lymphomas: PTCL, NOS and AITL
16.1 Introduction
16.2 Follicular helper T cells in the pathogenesis of AITL
16.3 Gene expression profiling insights in the classification and biology of PTCL, NOS and AITL
16.4 The genetic landscape of AITL and PTCL, NOS
16.5 Lessons from animal models
16.6 Concluding remarks
17. Extranodal NK/T-cell lymphoma
17.1 Introduction
17.2 General clinicopathologic features
17.3 Receptor expression
17.4 The role of EBV in pathogenesis
17.5 Genetic and epigenetic alterations
17.6 γδ T-cell
lymphoma
17.6.1 Cell of origin
17.6.2 Subtypes of lymphomas derived from γδ T
cells
17.6.3 Hepatosplenic γδ T
-cell lymphoma
17.6.4 Primary cutaneous γδ T
-cell lymphoma
17.6.5 Mucosal γδ T
-cell lymphoma
17.6.6 γδ T
-cell lymphoma in the intestine
17.7 Gene expression profiling analysis
17.8 JAK/STAT pathway activation
17.9 Concluding remarks
18. Lymphomas associated with viral infection
18.1 Introduction
18.2 Epstein–Barr virus (EBV)
18.2.1 Patterns of EBV latency
18.2.2 EBV mediated lymphomagenesis
18.2.3 Lymphomas associatedwith EBV infection
18.3 Kaposi’s sarcoma-associatedherpesvirus (KSHV)
18.4 KSHV-mediated lymphomagenesis
18.4.1 Lymphomas associated with KSHV infection
18.5 Human T-cell leukemia virus-1 (HTLV-1)
18.5.1 HTLV-1 mediated oncogenesis
18.5.2 Adult T-cell leukemia-lymphoma (ATL)
18.6 Hepatitis C virus
18.7 HIV and lymphomagenesis
18.8 Concluding remarks
19. Translating science into therapy of lymphoma
19.1 Introduction
19.2 Inhibition of the B-cell receptor signaling pathway
19.2.1 Historical overviewof BTK/PI3K inhibitors
19.2.2 Tumor hyperlymphocytosis
19.2.3 Diffuse large B-cell lymphoma
19.2.4 Follicular lymphoma
19.2.5 Waldenström’smacroglobulinemia (WM)
19.2.6 Marginal zone lymphomas
19.2.7 Chronic lymphocytic leukemia
19.2.8 Mantle Cell Lymphoma
19.3 Inducing the mitochondrial apoptosis pathway in lymphoma
19.4 Targeting ALK in lymphoma
19.5 Targeting immune cells in lymphoma
19.5.1 Lenalidomide
19.5.2 Immune checkpoints inhibitors
19.6 Targeting epigenetic deregulation
19.6.1 EZH2 inhibitors
19.6.2 IDH2
19.7 Concluding remarks
Index