The curious origins of angioimmunoblastic T-cell lymphoma

Abstract

Purpose of review: Once an obscure disease, recent studies have transformed our understanding of angioimmunoblastic T-cell lymphoma (AITL). In this review, we summarize new major advances in the genetics and biology of AITL.

Recent findings: Genome wide sequencing studies have dissected the repertoire of the genetic alterations driving AITL uncovering a highly recurrent Gly17Val somatic mutation in the small GTPase RHOA and major role for mutations in epigenetic regulators, such as TET2, DNMT3A and IDH2, and signaling factors (e.g., FYN and CD28). These findings support a multistep model of follicular T helper cell transformation in AITL and pinpoint novel candidates for the development of targeted therapies in this disease.

Summary: AITL originates from follicular T helper cells and is characterized by the presence of RHOA G17V mutation together with genetic alterations in TET2, DNMT3A, and IDH2. Research efforts now focus on the elucidation of the specific roles and interplay of these genetic alterations in the pathogenesis of AITL.

Figure 1. Normal development and malignant transformation of TFH cells

TFH cell differentiation is initiated by activation of CD4 naïve T cells by dendritic cells in presence of IL6, IL21 and IL12 leading to STAT3/STAT4 activation. Activation of ICOS induces the upregulation of BCL6 and CXCR5, allowing them to migrate to B cell follicles to induce germinal centers formation. Stimulation of TFH cells and antigen presentation by B cells leads to full development of TFH cells, whose mission is supporting B-cells and facilitating the generation of long-lived plasma cells and memory B cells. Malignant transformation of TFH leads to the development of AITL following a multistep tumor model where TET2 and/or DNMT3A mutations would be acquired first, followed by specification into the TFH lineage guided by expression of the RHOA G17V mutant and enhanced by hyper activation of the TCR signaling pathway. Deregulated expansion and/or function of TFH could induce the generation of cytokines (IL4, IL6, IL21 and IL10) which play a prominent role in the early stages of lymphoma progression and in setting the abundant inflammatory component of AITL tumor lesions.

Figure 2. Recurrent mutations in AITL

Schematic representation of the structure of the most frequently mutated proteins in AITL: RHOA, TET2, DNMT3A, IDH2, FYN and CD28. (Data adapted from Palomero et al, 2014 (for RHOA, TET2, DNMT3A, IDH2 and FYN) or Wang et al, 2015 (for CD28)).Black circles represent amino acid substitutions while open red circles indicate truncating mutations. G:GTP/GDP binding domain; Effector: effector interaction domain; NKXD: NKXD GTP-binding domain; CAAX: CAAX box prenylation domain; Cys: cysteine-rich domain; DSBH: double-stranded beta helix fold domain; PWWP: PWWP domain; PHD: plant homeodomain; Immunoglobulin domain: Ig variable region-like domain CD28 and CTLA4; TM, transmembrane domain. L: ligand interaction site; S2: SH2-binding motif; pink: S3: SH3-binding motifs; SH3: SH3 domain; SH2: SH2 domain.

Figure 3. Co-occurrence of frequent mutations in AITL

(a) Analysis of the mutational status of RHOA G17V, TET2, DNMT3A and IDH2 in a cohort of 120 AITL (information extracted from published data (–64)). Each column represents a patient sample; each row represent mutations in each of the genes of interest. (b) Quantification of the co-occurrence of mutations in RHOA G17V and epigenetic regulators. In the column on the right are represented the cases mutated for RHOA G17V, TET2, DNMT3A and IDH2 R172; on the upper row the co-occurrence indicated by the number of cases on the left category that also carry the mutation in the genes indicated on the top (n) and the percentage of co-occurrence calculated from the total number of cases [(%) in bold].

Figure 4. Targeted therapies in AITL

Schematic diagram depicting pharmacologic agents that target relevant proteins in AITL and TFH cells that could be used for personalized therapies against AITL lymphomas.