Abstract
Simple SummaryT-cell leukemia/lymphoma 1A (TCL1A) is a proto-oncogene that is mainly expressed in embryonic and fetal tissues, as well as in some lymphatic cells. It is frequently overexpressed in a variety of T- and B-cell lymphomas and in some solid tumors. In chronic lymphocytic leukemia and in T-prolymphocytic leukemia, TCL1A has been implicated in the pathogenesis of these conditions, and high-level TCL1A expression correlates with more aggressive disease characteristics and poorer patient survival. Despite the modes of TCL1A (dys)regulation still being incompletely understood, there are recent advances in understanding its (post)transcriptional regulation. This review summarizes the current concepts of TCL1A’s multi-faceted modes of regulation. Understanding how TCL1A is deregulated and how this can lead to tumor initiation and sustenance can help in future approaches to interfere in its oncogenic actions.Incomplete biological concepts in lymphoid neoplasms still dictate to a large extent the limited availability of efficient targeted treatments, which entertains the mostly unsatisfactory clinical outcomes. Aberrant expression of the embryonal and lymphatic TCL1 family of oncogenes, i.e., the paradigmatic TCL1A, but also TML1 or MTCP1, is causally implicated in T- and B-lymphocyte transformation. TCL1A also carries prognostic information in these particular T-cell and B-cell tumors. More recently, the TCL1A oncogene has been observed also in epithelial tumors as part of oncofetal stemness signatures. Although the concepts on the modes of TCL1A dysregulation in lymphatic neoplasms and solid tumors are still incomplete, there are recent advances in defining the mechanisms of its (de)regulation. This review presents a comprehensive overview of TCL1A expression in tumors and the current understanding of its (dys)regulation via genomic aberrations, epigenetic modifications, or deregulation of TCL1A-targeting micro RNAs. We also summarize triggers that act through such transcriptional and translational regulation, i.e., altered signals by the tumor microenvironment. A refined mechanistic understanding of these modes of dysregulations together with improved concepts of TCL1A-associated malignant transformation can benefit future approaches to specifically interfere in TCL1A-initiated or -driven tumorigenesis.
Highlights
Its aberrant overexpression was first identified in T-cell prolymphocytic leukemia (T-PLL) via genomic aberrations involving its locus at chromosome 14 [1]
Due to its specific expression in T-PLL among other mature T-cell lymphomas (MTCL) with prominent peripheral blood (PB) presentation, T-cell leukemia/lymphoma 1A (TCL1A) was established as a first-order marker of high specificity [46,55]
In non-neoplastic settings, its expression was utilized as a distinct prediction marker, as high TCL1A expression in peripheral blood mononuclear cells of patients undergone kidney transplantation correlated with tolerance after transplantation, which mainly results from a higher naïve B-cell population in tolerant patients
Summary
T-cell leukemia/lymphoma 1A (TCL1A) was first described as a proto-oncogene in hematological neoplasms between 1989 and 1994 [1,2,3] It is the prototype of a 3-paralogue gene family, further including TCL1B and mature T-cell proliferation 1 (MTCP1) [4]. In B-cell tumors, there is a virtual absence of such rearrangements [10] or gain-of-function mutations [11] involving the TCL1A locus. In these tumors, TCL1A expression parallels its regulation in non-neoplastic. This review summarizes the current knowledge on the spectrum of TCL1A’s modes of upstream regulations in normal and transformed lymphocytes, as well as in stem cells and solid tumors
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