RNA-Seq reveals the existence of a CDKN1C-E2F1-TP53 axis that is altered in human T-cell lymphoblastic lymphomas

Abstract

BackgroundPrecursor T-cell lymphoblastic lymphomas (T-LBL) are rare aggressive hematological malignancies that mainly develop in children. As in other cancers, the loss of cell cycle control plays a prominent role in the pathogenesis in these malignancies that is primarily attributed to loss of CDKN2A (encoding protein p16INK4A). However, the impact of the deregulation of other genes such as CDKN1C, E2F1, and TP53 remains to be clarified. Interestingly, experiments in mouse models have proven that conditional T-cell specific deletion of Cdkn1c gene may induce a differentiation block at the DN3 to DN4 transition, and that the loss of this gene in the absence of Tp53 led to aggressive thymic lymphomas.ResultsIn this manuscript, we demonstrated that the simultaneous deregulation of CDKN1C, E2F1, and TP53 genes by epigenetic mechanisms and/or the deregulation of specific microRNAs, together with additional impairing of TP53 function by the expression of dominant-negative isoforms are common features in primary human T-LBLs.ConclusionsPrevious experimental work in mice revealed that T-cell specific deletion of Cdkn1c accelerates lymphomagenesis in the absence of Tp53. If, as expected, the consequences of the deregulation of the CDKN1C-E2F1-TP53 axis were the same as those experimentally demonstrated in mouse models, the disruption of this axis might be useful to predict tumor aggressiveness, and to provide the basis towards the development of potential therapeutic strategiesin human T-LBL.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4304-y) contains supplementary material, which is available to authorized users.

Targeting the MAPK7/MMP9 axis for metastasis in primary bone cancer

“…3c and Supplementary File 3) where E2F transcription factor 1 (E2F1) was the hub gene because E2F1 mediates TP53-dependent apoptosis. This pathway is critical for the current study because of the TP53 −/− driver mutation described earlier [23].…”

lncRNA STEAP3-AS1 Modulates Cell Cycle Progression via Affecting CDKN1C Expression through STEAP3 in Colon Cancer

“… 48 For CDKN1C, its loss could be attributable to hyperactivation of p53 at the DN3–DN4 transition. 49 , 50 Also, it was reported that in quercetin- and cisplatin-treated cells, the expression of CDKN1C, CCNA2, CCND2 ,CCND3, CCNE1, and CDK2 could be simultaneously elevated. 51 Thus, we suspected there might be some interactions between STEAP3 and CDKN1C, and further studies are needed.…”

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“…Finally, besides epigenetic changes and signal-transduction modulation, regulation by microRNAs might be an additional mechanism contributing to p57 level control in a wide variety of solid and liquid tumors [ 141 ]. Particularly, miR25, miR221, and miR222 were reported as able to directly target CDKN1C RNA in gastric cancer [ 142 ], hepatocellular carcinoma (HCC), and human T-cell lymphoblastic lymphomas [ 143 ], and miR-92b has been reported as responsible for p57 downregulation in HCC tissues and cell lines, enhancing tumor radio-resistance to ionization radiation (IR)-based radiotherapy [ 144 ].…”