Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma

Abstract

Key Points TOX is aberrantly expressed in primary Sézary cells and its levels correlate with increased risk of disease-specific mortality. TOX knockdown promotes apoptosis and reduces cell proliferation in CTCL cells, partially through inducing p27 and p57.

TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia

“…Finally, studies of human T-ALL and xenograft studies revealed additional roles for TOX in regulating continued leukemia maintenance by specifically regulating cell cycle proliferation and apoptosis. These results are in keeping with known roles for TOX in regulating cell cycle in primary Sezary cells and Cutaneous T-cell Lymphoma where TOX knockdown led to cell cycle arrest and secondarily cell death (37). Collectively, our work has identified TOX as a new collaborating oncogenic driver in T-ALL and which likely exerts important and diverse functional effects in a large fraction of human T-ALLs.…”

“…Because TOX had been previously shown to regulate proliferation in primary Sezary cells and Cutaneous T-cell Lymphoma (37), our studies focused on uncovering additional roles for TOX in regulating DNA repair pathways. Remarkably, our endogenous TOX pull-downs and subsequent LC-MS mass spectrometry analysis uncovered potent interactions between TOX and KU70/KU80, prompting further investigation into roles for TOX in regulating DNA repair and NHEJ.…”

Malignant TOXication of T cells

“…Interestingly, they also display aberrant expression of other thymic genes such as the B lymphoid kinase (BLK) and cancer-testis genes, which are not expressed in mature peripheral and skin resident T cells. [5][6][7] In concert with the present study by Huang et al, 1 these findings could suggest that malignant T cells either arise from a transformed thymic stem cell or become deregulated, "reopening" a thymic expression program (see figure). The fact that malignant T cells usually display a fully completed TCR rearrangement, a functional TCR CD3 complex (at least in the initial stages of the disease), and a phenotype similar to that of a mature T cell argues against an early thymic stem cell origin.…”

“…The big question is what drives transformation from an indolent skin condition with a good prognosis and a normal life expectancy to a highly aggressive cancer with a poor prognosis. Here, Huang et al 1 show that aberrant expression of thymocyte selection-associated high-mobility group (HMG) box gene TOX is associated with increased disease-specific mortality in patients with Sézary syndrome, a leukemic variant of CTCL. Importantly, TOX drives mitogenesis and survival of malignant T cells in vitro and tumor formation in vivo.…”

“…The effect on cell cycle progression is notably mediated through a TOX-dependent repression of the 2 cyclindependent kinase inhibitors CDKN1B and CDKN1C, providing the first evidence of a direct link between TOX and these cell cycle regulators. 1 TOX is a nuclear factor which is expressed in the thymus in a stage-specific and regulated manner and believed to play an important role during development of double-positive thymocytes.…”