Co-expression of TNF receptors 1 and 2 on melanomas facilitates soluble TNF-induced resistance to MAPK pathway inhibitors.

Background: The effectiveness of MAPK pathway inhibitors (MAPKi) used to treat patients with BRAF-mutant melanoma is limited by a range of resistance mechanisms, including soluble TNF (solTNF)-mediated NF-kB signaling. solTNF preferentially signals through type-1 TNF receptor (TNFR1), however, it can also bind to TNFR2, a receptor that is primarily expressed on leukocytes. Here, we investigate the TNFR2 expression pattern on human BRAF melanomas and its role in solTNF-driven resistance reprogramming to MAPKi.

The leukemic oncoprotein NPM1-RARA inhibits TP53 activity.

The variant acute promyelocytic leukemia (APL) translocation t(5;17)(q35;q21) fuses the N-terminus of nucleophosmin (NPM1) to the retinoic acid receptor alpha (RARA). We found that ectopic NPM1-RARA expression decreased TP53 protein levels in target cells. NPM1-RARA impaired TP53-dependent transcription.

Interaction with RXR is necessary for NPM-RAR-induced myeloid differentiation blockade.

The t(5;17)(q35;q21) APL variant results in expression of a fusion protein linking the N-terminus of nucleophosmin (NPM) to the C-terminus of the retinoic acid receptor alpha (RAR). We have previously shown that NPM-RAR is capable of binding to DNA either as a homodimer or heterodimer with RXR. To determine the biological significance of NPM-RAR/RXR interaction, we developed two mutants of NPM-RAR that showed markedly diminished ability to bind RXR.

NPM-RAR, not the RAR-NPM reciprocal t(5;17)(q35;q21) acute promyelocytic leukemia fusion protein, inhibits myeloid differentiation.

The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the nucleophosmin (NPM) gene at 5q35 with the retinoic acid receptor alpha (RARA) at 17q12-22. We have previously shown that leukemic cells express both NPM-RAR and RAR- NPM reciprocal translocation products. In this study we investigated the potential role of both proteins in modulating myeloid differentiation.

The NPM-RAR fusion protein associated with the t(5;17) variant of APL does not interact with PML.

The PML protein localizes to regions of the nucleus known as nuclear bodies or PODs. However, in t(15;17) Acute Promyelocytic Leukemia (APL) blasts, PML is found in a micro-punctate pattern. In order to test the hypothesis that delocalization of PML from PODs is necessary for APL, we investigated the interaction of the t(5;17) APL fusion protein NPM-RAR with PML.