The Role of NOTCH1, GATA3, and c-MYC in T Cell Non-Hodgkin Lymphomas

Abstract

Lymphomas are heterogeneous malignant tumours of white blood cells characterised by the aberrant proliferation of mature lymphoid cells or their precursors. Lymphomas are classified into main types depending on the histopathologic evidence of biopsy taken from an enlarged lymph node, progress stages, treatment strategies, and outcomes: Hodgkin and non-Hodgkin lymphoma (NHL). Moreover, lymphomas can be further divided into subtypes depending on the cell origin, and immunophenotypic and genetic aberrations. Many factors play vital roles in the progression, pathogenicity, incidence, and mortality rate of lymphomas. Among NHLs, peripheral T cell lymphomas (PTCLs) are rare lymphoid malignancies, that have various cellular morphology and genetic mutations. The clinical presentations are usually observed at the advanced stage of the disease. Many recent studies have reported that the expressions of NOTCH1, GATA3, and c-MYC are associated with poorer prognosis in PTCL and are involved in downstream activities. However, questions have been raised about the pathological relationship between these factors in PTCLs. Therefore, in this review, we investigate the role and relationship of the NOTCH1 pathway, transcriptional factor GATA3 and proto-oncogene c-MYC in normal T cell development and malignant PTCL subtypes.

Keywords: GATA3; NHL; NOTCH1; PTCL; c-MYC; lymphoma.

Figure 1

Molecular events involved in regulating T cell subtypes development: (a) T cell receptor (TCR) CD4 binds with major histocompatibility complex class II (MHCII); (a.1) Th1 cells being induced in response to the activation of specific intracellular INF-ϒ and IL-12 receptor pathways, that are mediated by STAT1 and STAT4, respectively; (a.2) Th2 cells are induced in response to mainly IL-2 and IL-4 receptor ligation and activation of STAT5 and STAT6 pathways, respectively; (a.3) Th17 cells are induced in response to activation of intracellular pathways of IL-6 or IL-21, and TGF-β receptors, and their activation mediated through STAT3 pathway for IL-6 or IL-21, and SMAD2/3 pathway for TGF-β; (a.4) Th22 cells are induced in response to IL-6 and TNF-α receptor ligation and activation of STAT3 pathways that lead to induction of Th22 master transcription factor AhR (the aryl hydrocarbon receptor); (a.5) Regulatory T cells (Treg) are induced in response to the activation of intracellular pathways of IL-2 and TGF-β receptors, that are mediated by STAT5 pathway for IL-2 and SMAD2/3 pathway for TGF-β; (a.6) Th9 cells are induced in response to activation of intracellular pathways of IL-4 and TGF-β receptors, that are mediated by STAT6 pathway for IL-4 and SMAD2/3 pathway for TGF-β; (a.7) T follicular helper (Tfh) cells are induced in response to activation of intracellular pathways of IL-6, IL-12, IL-21, and Activin A receptors, that are mediated by STAT3 pathway for Interleukins receptors, and SMAD2/3 pathway for Activin A receptor; (b) T cell receptor (TCR) CD8 bind with major histocompatibility complex class I (MHCI); (b.1) Tc1 cells induced in response to activation of intracellular pathways of INF-ϒ and IL-12 receptors, that are mediated by STAT1 and STAT4, respectively. As a result of STATs pathway activation, they lead eventually to induction of master transcription factor ECOMES and T-bet that encoded by the Tbx21 gene, production of INF-ϒ, reinforces the Tc1 polarization, creating a positive feedback loop, and suppresses the alternative differentiation programs; (b.2) Tc2 cells induced in response to mainly IL-2 and IL-4 receptor ligations, and activation of STAT5 and STAT6 pathways, respectively. Appropriate STATs signalling leads to induction of master transcription factor GATA3, Tc2 polarization, antagonizes Tc1 polarization, and cytokines produced includes IL-4, IL-5, and IL-13, as well as effector molecules, such as granzymes and perforin; (b.3) Tc17 cells are induced in response to activation of intracellular pathways of IL-6 or IL-21, and TGF-β receptors, that is mediated by STAT3 pathway for IL-6 or IL-21 and SMAD2/3 pathway for TGF-β; (b.4) Tc22 cells are induced in response to activation of intracellular pathway IL-6 and TNF-α receptors, that are mediated by STAT3 pathway; (b.5) Tc9 cells are induced in response to activation of intracellular pathways of IL-4 and TGF-β receptors, that were mediated by STAT6 pathway for IL-4 and SMAD2/3 pathway for TGF-β.

Figure 2

Niche of T cell selection and development. (a) In bone marrow (BM) hematopoietic stem cells differentiate to multipotent progenitor (MPP) that subsequently derived to subset called early lymphoid progenitors (ELP) or lymphoid primed multipotent progenitors (LMPP). LMPP differentiate into further downstream developmental stages, common lymphoid progenitor (CLP) that migrates from the bone marrow compartments into thymus through blood stream via the action of chemokines, cell adhesion molecules, and CCL25/CCR9, CCL19-CCL21/CCR7 receptors; (b) Cortical DP cells that express αβTCR interacting with MHC molecules presenting on edoncortical thymic epithelial cells (cTECs), receive critical survival signals that are required to further process of differentiation. In other words, T cells election and acquisition of MHC restrictions referred to as positive selection. Double positive (DP) cells begin expressing the chemokine receptor CCR7 and migrate to the thymic medulla. In the medulla, TCRs-DP T cells interact with antigen-presenting cells, such as mTECs and dendritic cells, and differentiate into CD4 or CD8 single-positive (SP). The interactions of high-affinity T cells TCRs to self-peptide MHC, normally result in either deleted of autoreactive cells by apoptosis that referred to negative selection or destined to become regulatory T cells through undergoing agonist selections; (c) Phases of early T cell development. ETPs in thymus undergo three distinct phases based on the status of T lineage commitment and NOTCH dependency; (c.1) Thymus stroma secrets cytokines that act as transcriptional factors include IL-7, FLT3, and cKit. These cytokines initiate the expression of some genes, such as GATA3, Hes1, and Tcf, through activation of NOTCH signalling pathway; (c.2) these genes beside RUNX1 promote expansion of pre-commitment precursor as well as turn on transcriptional repressor Bcl11b in the late DN2a; (c.3) T cell passes from cell commitment and characterized with NOTCH-dependent, slow proliferation and TCR rearrangement. BCL11B turns on leads to c-Kit down-regulation, IL-7R signalling desensitization by E proteins, and DN2b cells survival become strictly NOTCH-dependent. E protein-dependent genes are recombination activating gene 1 (Rag1), Rag2, as well as Ptcra (encoding pre-TCRɑ), Cd3e (encoding CD3), and TCRβ (or TCRϒ and TCRδ) gene rearrangement; (c.4) Achieved V(D)J rearrangement for the TCRβ gene, express pre-TCR and the cells proceed to the DN3b stage after completion of β-selection, followed by transition into DN3/4 and cells gaining ability to receive signals through pre-TCR, transition from Notch-dependent to Notch-independent and leads to rapidly turning off Notch target genes and IL-7R expression; (c.5) Cells transition into DP (CD4⁺ CD8⁺); (c.6) TCRα gene in DP rearrangement differentiates into SP cells, expressing ɑβTCR, by the action of chemokine signalling, such as CXCL12/CXCR4, and up-regulation of new transcription factors; IKZF3 (Aiolos) and RORϒt.

Figure 3

Experimental evidence of the determinate role of GATA3 in T cell development through using different experimental methods: (a) RNA interference used for reducing GATA3 during T cell development, inducing GATA3 conditional knocking out in mouse model, and check gene expression of other functional genes; (b) Inserting LacZ reporter for inducing GATA3 conditional knocking out in mouse model and chimeric mice generation; (c) Antisense oligonucleotide used for block ability of GATA3 gene to make proteins; (d) Cre-loxp system used for GATA3 conditional deletion of GATA3 in DN and DN2; and (e) Thymic lymphomas in transgenic mice used for enforce GATA3 expression during T cell development, and GATA3 conditional knocking out in mouse model.

Figure 4

Expression of GATA3 during T cell development. Four-color intracellular detection of GATA3 in early DN thymocyte subsets from B6 adult mice they showed GATA 3 protein levels during T cell development besides defined subset expression of c-Kit, CD44, and CD25.

Figure 5

Relationship and predicted relationship of NOTCH1, GATA3 and c-MYC in T cell lymphoma development by using Ingenuity Pathway Analysis (IPA), QIAGEN.