Biology subjects

Mologni, L.

Publications and source records attributed to Mologni, L..

5 recordsLinked to original sources

bioRxiv2026

A Novel ACLY Inhibitor Induces Transcriptional and Metabolic Reprogramming to Overcome Tyrosine kinase inhibitor Resistance in Lymphoma

Background: Metabolic plasticity contributes to therapeutic resistance in T-cell lymphoma, but the metabolic dependencies underlying tyrosine kinase inhibitor (TKI) resistance remain poorly understood. ATP citrate lyase (ACLY), which converts citrate to cytosolic acetyl-CoA, links glucose metabolism to lipogenesis and acetylation-dependent regulation. We hypothesized that ACLY represents an actionable metabolic vulnerability in lymphoma. Methods: Structure-guided drug discovery and biochemical screening were used to identify the novel ACLY inhibitor VCB1. VCB1 was evaluated against recombinant human ACLY and in TKI-sensitive and TKI-resistant lymphoma models. Antitumor activity was assessed by proliferation, cell-cycle analysis, apoptosis, and immunoblotting, followed by integrated transcriptomic, metabolomic, and lipidomic profiling. Results: Our xenograft study showed that ACLY dependence in ALK+ALCL. We discovered novel ACLY inhibitor VCB1 directly inhibited recombinant ACLY with uM potency (IC, 0.9 uM) and strongly suppressed lymphoma cell growth. In ALK inhibitor-sensitive SUPM2, VCB1 showed an IC of 0.299 uM and retained potency in lorlatinib-resistant SUPM2-LR1000 cells (1.62 uM), whereas BMS-303141 was substantially less active (17.46 and 22.07 uM). VCB1 similarly inhibited BTK inhibitor sensitive and resistant mantle cell lymphoma cell growth (IC, 0.28 and 0.278 uM), compared with BMS-303141 (30.5 and 37.01 uM). Multi-omics profiling revealed suppression of de novo lipogenesis, including ACACA, FASN, and PPARGC1B, together with extensive remodeling of triglyceride, phospholipid, cardiolipin, ceramide, and acylcarnitine species and increased expression of fatty-acid oxidation genes. VCB1 activated the integrated stress response (ISR), inducing ATF4, PPP1R15A, DDIT3, DDIT4 and SESN2, while disrupting purine and pyrimidine metabolism and reducing nucleotide biosynthetic genes, including CAD, DHODH, UCK2, and ATIC. VCB1 further activated an ACLY/ISR/CHAC1 axis associated with reduced GCLC/GCLM expression, glutathione depletion, and a decreased GSH/GSSG ratio, indicating impaired redox homeostasis. TKI-resistant cells exhibited distinct lipid-metabolic remodeling consistent with metabolic plasticity. VCB1 also altered immune-regulatory programs involving PDCD1, TIGIT, CD247, CD226, NFATC2, and inflammatory cytokines. Functionally, VCB1 induced cell cycle arrest and apoptosis. Conclusions: ACLY represents an integrated metabolic and signaling vulnerability in lymphoma. VCB1 suppresses lymphoma growth across TKI-sensitive and resistant models by disrupting lipid and nucleotide metabolism, metabolic adaptation and ISR and redox homeostasis supporting ACLY inhibition as a therapeutic strategy for TKI-resistant lymphoma.

cancer biology↗

bioRxiv2026

Tyrosine phosphorylation and dimerization cooperatively activate NAMPT to enable NAD+ synthesis in cancer

Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, is frequently upregulated in cancer, yet mechanisms regulating its catalytic activity remain undefined. We identify NAMPT as a direct substrate of multiple proto-oncogenic tyrosine kinases, including ALK, insulin receptor, IGF1R, and PDGFRA. Phosphoproteomics identified NAMPT Y188 as the major phosphorylation site, including the oncogenic fusion kinase NPM1::ALK. NAMPT interacted with NPM1::ALK in the cytoplasm, nucleus, and mitochondria, while Y188 phosphorylation enhanced catalytic activity, NMN/NAD biosynthesis, and downstream metabolism. Conversely, the Y188F mutant reduced enzymatic activity, proliferation, and clonogenicity, whereas disrupting dimerization similarly impaired phosphorylation and function. Interactome analyses showed phosphorylation and dimerization cooperatively remodel NAMPT-associated networks, enriching phosphorylated dimers for metabolic/redox regulators and monomeric NAMPT for ribosome biogenesis. NAMPT inhibition suppressed the growth of both ALK inhibitor-sensitive and -resistant lymphoma cells and enhanced the efficacy of ALK inhibition, revealing kinase-dependent NAMPT activation as a metabolic vulnerability in oncogene-driven cancers.

cancer biology↗

bioRxiv2025

A Novel Allosteric Inhibitor Targeting IMPDH2 at Y233 Overcomes Resistance to Tyrosine Kinase Inhibitors in Lymphoma

Inosine monophosphate dehydrogenase-2 (IMPDH2) is a rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides and is often overexpressed in hematologic malignancies and solid tumors. However, its regulatory mechanisms in cancer remain poorly understood. Here, we identify IMPDH2 as a direct substrate of the oncogenic kinases ALK and SRC, which phosphorylate tyrosine 233 (Y233) within the enzymes allosteric Bateman domain. Using peptide-based mutagenesis and enzymatic assays, we demonstrate that Y233 phosphorylation is essential for IMPDH2 activity. We found that phosphoinositide-3-phosphate (PI3P), a signaling phospholipid, selectively binds to and inhibits IMPDH2, but not its isoform IMPDH1, revealing a novel lipid-mediated, isoform-specific regulatory mechanism. Next, we conducted structure-based virtual screening and identified a potent allosteric inhibitor of IMPDH2, compound 10 (comp-10), with an IC of 260 nM. Comp-10 significantly impairs cell proliferation in ALK-positive anaplastic large cell lymphoma (ALCL) cell lines, including those resistant to the ALK inhibitors crizotinib and lorlatinib, and outperformed the FDA-approved IMPDH inhibitor mycophenolic acid. These findings reveal the dual regulation of IMPDH2 through tyrosine phosphorylation and binding to PI3P, and describe the discovery of a new IMPDH2 inhibitor, suggesting a potential therapeutic strategy to overcome resistance to tyrosine kinase inhibitors.

cancer biology↗

bioRxiv2023

Evolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients

By leveraging the ever-increasing availability of cancer omics data and the continuous advances in cancer data science and machine learning, we have discovered the existence of cancer type-specific evolutionary signatures associated with different disease outcomes. These signatures represent "favored trajectories" of acquisition of driver mutations that are repeatedly detected in patients with similar prognosis. In this work, we present a novel framework named ASCETIC (Agony-baSed Cancer EvoluTion InferenCe) that extracts such signatures from NGS experiments generated by different technologies such as bulk and single-cell sequencing data. In our study, we applied ASCETIC to (i) single-cell sequencing data from 146 patients with distinct myeloid malignancies and bulk whole-exome sequencing data from 366 acute myeloid leukemia patients, (ii) multi-region sequencing data from 100 early-stage lung cancer patients from the TRACERx project, (iii) whole-exome/genome sequencing data from more than 10,000 Pan-Cancer Atlas samples, and (iv) targeted bulk sequencing data from more than 25,000 MSK-MET metastatic patients (both datasets including multiple cancer types). As a result, we extracted different cancer (sub)type-specific single-nucleotide variants evolutionary signatures associated with clusters of patients with statistically significant different prognoses. In addition, we conducted several validations using diverse and previously unexplored datasets to evaluate the reliability and applicability of the evolutionary signatures extracted by ASCETIC. Such analyses provided evidence of the robustness and generalizability of the identified evolutionary patterns.

genetics↗

bioRxiv2022

Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition

Within the chromatin, distal elements interact with promoters to regulate specific transcriptional programs. Histone acetylation, interfering with the net charges of the nucleosomes, is a key player in this regulation. Here, we report that the onco-protein SET is a critical determinant for the levels of histone acetylation within enhancers. We disclose that conditions in which SET is accumulated, including the severe Schinzel-Giedion Syndrome (SGS), are characterized by a failure in the usage of the distal regulatory regions typically employed during fate commitment. This is accompanied by the usage of alternative enhancers leading to a massive rewiring of the distal control of the gene transcription. This represents a (mal)adaptive mechanism that, on one side, allows to achieve a certain degree of differentiation, while on the other affects the fine and corrected maturation of the cells. Thus, we propose the differential in cis-regulation as a contributing factor to the pathological basis of the SET-related disorders in humans, including SGS, neurodevelopmental disorders, myeloproliferative diseases, and cancer.

developmental biology↗