Biology subjects

Verrecchia, A.

Publications and source records attributed to Verrecchia, A..

5 recordsLinked to original sources

bioRxiv2022

Oxidative stress potentiates the therapeutic action of a mitochondrial complex I inhibitor in MYC-driven B-cell lymphoma

MYC is a key oncogenic driver and an adverse prognostic factor in multiple types of cancer, including diffuse large B-cell lymphoma (DLBCL). Yet, MYC activation also endows cancer cells with a series of metabolic dependencies, which can provide strategic points for targeted pharmacological intervention. We recently reported that targeting the mitochondrial electron transport chain (ETC) complex I with the small molecule inhibitor IACS-010759 selectively killed MYC-overexpressing lymphoid cells. Here, we unravel the mechanistic basis for this synthetic-lethal interaction and exploit it to improve the anti-tumoral effects of ETC inhibition. In a mouse B-cell line, MYC hyperactivation and IACS-010759 treatment added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced by targeted pharmacological intervention, with either inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to contribute pro-oxidant effects when administered at high doses. In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, ETC inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and other MYC-driven cancers. Key point #1MYC and the ETC complex I inhibitor IACS-010759 elicit different reactive oxygen species (ROS) that cooperate to disrupt redox homeostasis. Key point #2Further boosting of oxidative stress with high doses of ascorbate increases the killing of MYC-driven lymphoma xenografts by IACS-010759.

cancer biology↗

bioRxiv2021

Polycomb Group Ring Finger Protein 6 suppresses Myc-induced lymphomagenesis

Max is an obligate dimerization partner for the Myc transcription factors and for several repressors, such as Mnt, Mxd1-4 and Mga, collectively thought to antagonize Myc function in transcription and oncogenesis. Mga, in particular, is part of the variant Polycomb group repressive complex PRC1.6. Here, we show that ablation of the distinct PRC1.6 subunit Pcgf6 - but not Mga - accelerates Myc-induced lymphomagenesis in E{micro}-myc transgenic mice. Unexpectedly, however, Pcgf6 loss shows no significant impact on transcriptional profiles, in neither pre-tumoral B-cells, nor lymphomas. Altogether, these data unravel an unforeseen, Mga- and PRC1.6-independent tumor suppressor activity of Pcgf6.

cancer biology↗

bioRxiv2020

Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma

Multiple molecular features, such as activation of specific oncogenes (e. g. MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL). Understanding the relationships between these features and their possible exploitation toward disease classification and therapy remains a major priority in the field. Here, we report that MYC activity in DLBCL is closely correlated with - and most likely a driver of - gene signatures related to Oxidative Phosphorylation (OxPhos). On this basis, we hypothesized that enzymes involved in Oxidative Phosphorylation, and in particular electron-transport chain (ETC) complexes, might constitute tractable therapeutic targets in MYC-associated lymphoma. Indeed, our data show that MYC sensitizes B-cells to IACS-010759, a selective inhibitor of ETC complex I. Mechanistically, IACS-010759 activates an ATF4-driven Integrated Stress Response (ISR), engaging the intrinsic apoptosis pathway through the transcription factor CHOP. In line with these findings, IACS-010759 shows synergy with the BCL2 inhibitor venetoclax against double-hit lymphoma (DHL), a high-grade form of DLBCL with concurrent activation of MYC and BCL2. Similarly, in BCL2-negative lymphoma cell lines, inhibition of the BCL2-related protein Mcl-1 potentiates killing by IACS-010759. Altogether, ETC complex I inhibition engages the ISR to lower the apoptotic threshold in MYC-driven lymphomas and, in combination with select BCL2-family inhibitors, provides a novel therapeutic principle against this aggressive DLBCL subset. Statement of significanceThis work points to OxPhos as a key MYC-activated process and a tractable therapeutic target toward personalized treatment of high-grade DLBCL, providing strong context-dependent cooperation with BH3-mimetic compounds.

cancer biology↗

bioRxiv2020

Integrated requirement of non-specific and sequence-specific DNA binding in MYC-driven transcription

Eukaryotic transcription factors recognize specific DNA sequence motifs, but are also endowed with generic, non-specific DNA-binding activity: how these binding modes are integrated to determine select transcriptional outputs remains unresolved. We designed mutants of the MYC transcription factor bearing substitutions in residues that contact either the DNA backbone or specific bases within the consensus binding motif (E-box), and profiled their DNA-binding and gene-regulatory activities in murine cells. Our data reveal that non-specific DNA binding is required for MYC to engage onto active regulatory elements in the genome, preceding sequence recognition; beyond merely stabilizing MYC onto select target loci, sequence-specific binding contributes to its precise positioning and - most unexpectedly - to transcriptional activation per se. In particular, at any given binding intensity, promoters targeted via the cognate DNA motif were more frequently activated by MYC. Hence, seemingly promiscuous chromatin interaction profiles actually encompass diverse DNA-binding modalities, driving defined, sequence-dependent transcriptional responses.

molecular biology↗

bioRxiv2019

An early Myc-dependent transcriptional program underlies enhanced macromolecular biosynthesis and cell growth during B-cell activation

Upon activation, lymphocytes exit quiescence and undergo substantial increases in cell size, accompanied by activation of energy-producing and anabolic pathways, widespread chromatin decompaction and elevated transcriptional activity. These changes depend upon prior induction of the Myc transcription factor, but how Myc controls them remains unclear. We addressed this issue in primary mouse B-cells, based on conditional deletion of the c-myc gene, followed by LPS stimulation. Myc was rapidly induced, became detectable on virtually all active promoters and enhancers, but had no direct impact on global transcriptional activity. Instead, Myc contributed to the swift up- and down-regulation of several hundred genes, including many known regulators of the aforementioned cellular processes. Myc-activated promoters were enriched for E-box consensus motifs, bound Myc at the highest levels and showed enhanced RNA Polymerase II recruitment, the opposite being true at down-regulated loci. Remarkably, the Myc-dependent signature identified in activated B-cells was also enriched in Myc-driven B-cell lymphomas: hence, besides modulation of new cancer-specific programs, the oncogenic action of Myc may largely rely on sustained deregulation of its normal physiological targets.

cancer biology↗