TABLE 5-1 Cell of Origin (COO) and Most Common Genetic Aberrations in the T-Cell Lymphomas | ||||||||||||||||||||||||||||||||||||||
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Molecular Biology of T-Cell Lymphoma
Molecular Biology of T-Cell Lymphoma
Anjali Mishra
Pierluigi Porcu
INTRODUCTION
T-cell lymphomas represent a group of lymphoproliferative disorders of T-cell origin. T-cell lymphomas tend to be rare, heterogeneous, and more aggressive than their B-cell counterparts. Although classified under a single disease entity, T-cell lymphomas tend to present cellular heterogeneity that renders broad generalization of these lymphomas difficult.1,2,3 The T-cell lymphoma classification has evolved over the past two decades and, under the aegis of the World Health Organization (WHO), is now based on cell morphology, immunophenotype, genetics, and molecular and clinical features.4 Because T cells are complex and exhibit a variety of phenotypes with different functions and localizations, it is not surprising that the range of lymphomas of T-cell origin is similarly diverse. This complexity can lead to difficulty in ascertaining the origins and classification of a tumor, as exemplified by the large “not otherwise specified” exclusion class of T-cell lymphoma.1
In this chapter, we will briefly discuss the major types of T-cell lymphoma, describing the major molecular markers, pathways, and genes that best characterize them (Table 5-1). We will then outline the major underlying themes behind T-cell lymphomas as a whole. The molecular biology of T-cell lymphomas remains an area of vigorous research, and our understanding of the finer processes remains in flux; however, here we attempt to present the general consensus that has been established on this point.
MOLECULAR FEATURES OF T-CELL LYMPHOMA
Angioimmunoblastic T-Cell Lymphoma
Angioimmunoblastic T-cell lymphoma (AITL) is a rare, aggressive T-cell lymphoma of mature CD4+ T cells that accounts for 15% to 20% of peripheral T-cell lymphomas and 1% to 2% of all non-Hodgkin lymphoma cases worldwide. The neoplastic cells are thought to arise from follicular helper T (TFH) cells, because of their expression of CXCR5, BCL6, CD10, CXCL13, CD154, PD1, CD40L, NFATC1, ICOS, and SAP.1,5,6 Their CD4+CD57+ phenotype also matches the purported cell of origin, and the functional profile of normal TFH cells explains the principal clinical manifestations of AITL, which include B-cell activation, hypergammaglobulinemia, and autoimmunity.1 High expression of CXCL13 is thought to be a major factor in disease behavior. CXCL13 is a chemokine that recruits B cells and stimulates their proliferation. This is an important function of TFH cells in a normal germinal center and is likely a major contributor to the involvement of nonneoplastic cells in AITL—one study found almost 90% of genes in the AITL signature to arise from nonneoplastic cells.1 ICOS, CD40L, OX40, and IL21, also overexpressed in AITL, have been linked to the same phenotype.7 VEGF is commonly overexpressed in AITL, leading to the disease’s high degree of vascularization.1 CD10 has been identified as a regulator of apoptotic pathways, so it has been postulated that CD10 expression in AITL is an indicator of abnormal apoptosis in AITL.7,8 Chromosomal aberrancies are common in AITL, being found in up to 90% of cases.6 Common abnormalities include trisomies 3, 5, and 21, gain of X, and loss of 6q.6 Recently, mutations of the TET2 and IDH2 genes were found in 47% and 45% of AITL, respectively.9,10 TET2 mutations were found associated with advanced stage and unfavorable outcome. The clinical impact of molecular signatures in AITL was explored by Iqbal et al. Their study shows that high expression of genes associated with immunosuppressive signatures (tolerogenic dendritic cells) and proliferation (PDGFRα/β) predicts poor prognosis in AITL.
Anaplastic Large-Cell Lymphoma
Anaplastic large-cell lymphoma (ALCL) is a non-Hodgkin T-cell lymphoma that can exhibit either systemic or cutaneous distribution. It is commonly divided into three subtypes: ALK+, systemic ALK−, and cutaneous. ALCL is thought to arise from activated cytotoxic T cells, as exhibited by expression of TIA-1, granzyme B, and perforin.1,6
ALK+ cells often exhibit defective expression of many T-cell antigens, with CD2, CD4, and CD45 being the most commonly preserved.1,6 ALK− tumors tend to preserve more of these antigens, but express cytotoxic markers less frequently than ALK+.6 ALK+ ALCL is characterized by a gene translocation between the gene for the tyrosine kinase receptor ALK at 2p23 and various other genes, creating a chimeric fusion protein with the cytoplasmic domain of ALK fused to part of another protein, leading to constitutive ALK activation.1 The most common translocation involves ALK and nucleophosmin (NPM) on chromosome 5q35.1 ALK chimeras have been demonstrated to act as oncogenes by inducing proliferation and survival through interactions with the ERK, JAK3-STAT3, and PI3K-Akt pathways.1,11 The JAK3-STAT3 pathway is particularly important, as about two-thirds of the genes regulated by ALK are also dependent on STAT3.6 Additional genes of interest in ALK+ ALCL include CEBPB, a transcription factor that has been demonstrated as a critical gene for cell proliferation and survival, and SerpinA1, a serine protease inhibitor linked to invasion.1,6 In addition to the characteristic ALK translocation, ALK+ ALCL has been found to commonly exhibit chromosomal gain of 17p and losses of 4q and 11q.6,12
ALK− ALCL is morphologically and immunophenotypically similar to ALK+ ALCL, but is considered a distinct subtype with distinct molecular features and poorer prognosis. ALK− ALCL commonly exhibits chromosomal imbalances, particularly gains of 1q and 6p.12 Generally, ALK− karyotypes tend to be more complex than ALK+, reflecting the lack of a strong driving force provided by ALK chimeras—the ALK oncogene may drive transformation with a limited number of additional defects compared with what is necessary for ALK− cells.11 This increased frequency of chromosomal imbalances has also been associated with the poorer clinical outcomes of ALK−, compared with ALK+ ALCL.11 Cutaneous ALCL is a type of ALK− ALCL that differs from systemic ALCL primarily in its expression of the cutaneous lymphocyte antigen (CLA).13 It also lacks mucin 1 (MUC1), which systemic ALCL generally expresses.13
All types of ALCL are positive for CD30.6 CD30 is an important gene for ALCL by contributing to tumorigenesis and cell survival by activating the NF-κB and ERK pathways.14 Its overexpression in tumors has been linked to hypomethylation in the CD30 promoter or overexpression of JUNB, with which it forms a positive feedback loop.14
Apoptosis pathways have proven to be very important in ALCL prognosis. Survivin, a protein of the inhibitor of apoptosis (IAP) family that inhibits both intracellular and extracellular apoptotic pathways, has also been identified as a major factor in both ALK+ and ALK− ALCL.15 It has been identified as a target of the STAT3 pathway, which is activated in ALK+ ALCL, and has also been identified in a subset of ALK− ALCL.15 Survivin expression is associated with poorer prognosis, possibly by inhibiting chemotherapy-induced apoptosis.15 Caspase 3, Bcl-2, and PI9 are three more apoptosis-related indicators of ALCL prognosis.16 Caspase 3 is an effector caspase in the apoptosis pathway, whereas Bcl-2 and PI9 are both negative regulators of apoptosis.16 In ALCL, CASP3 is an indicator of good prognosis and is more commonly expressed in ALK+ ALCL.16 Both Bcl-2 and PI9 are indicators of poor prognosis and are almost exclusively found in ALK− ALCL.16 The differences in expression of these three genes may be another explanation for prognostic differences between ALK+ and ALK− ALCL. CD56 has been identified as a marker of worse prognosis, regardless of ALK status.17,18
