Biology subjects

Neri, A.

Publications and source records attributed to Neri, A..

5 recordsLinked to original sources

bioRxiv2025

Asymmetric induction of IL-23R by CpG and IL-15 in proliferative CLL fractions highlights intraclonal heterogeneity in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is sustained by complex interactions with the microenvironment, which provides signals for leukemic cell survival and proliferation. Among these, cytokines of the IL-12 family have emerged as relevant regulators of immune responses and tumor biology, yet their contribution to CLL remains incompletely defined. Previous studies showed that CLL cells can acquire responsiveness to IL-23 after T cell-dependent stimulation with CD40L, raising the question of whether T cell-independent signals can similarly induce functional receptor expression. Here we investigated the effect of CpG oligodeoxynucleotides, alone or in combination with interleukin-15 (IL-15), on IL-12 family receptor expression in CLL cells. We found that CpG + IL-15 stimulation significantly increased IL-23R and IL-12R{beta}1 expression, while IL-12R{beta}2 remained largely unresponsive. As a consequence, the complete IL-23 receptor complex was robustly induced, whereas IL-12 receptor assembly was only marginally enhanced. This skewing toward IL-23 rather than IL-12 signaling suggests that innate immune stimuli preferentially promote pathways supporting inflammation and survival, while limiting tumor-suppressive IL-12 responsiveness. Analysis of intraclonal heterogeneity revealed an asymmetric distribution of IL-23R among CXCR4/CD5-defined subfractions: the proliferative fraction, representing recently divided cells, expressed higher levels of IL-23R compared to the resting fraction. These findings suggest that IL-23 responsiveness is particularly enriched in the proliferating compartment of the leukemic clone. Overall, our results indicate that CpG and IL-15 stimulation drive a selective expansion of IL-23 signaling capacity in CLL, with preferential engagement of proliferative subfractions. This imbalance between IL-23 activation and insufficient IL-12R{beta}2 induction may represent a critical pathogenic mechanism and a potential therapeutic target.

cancer biology↗

bioRxiv2024

Genotypic identification of polyclonal plasma cells in plasma cell dyscrasias shows an aberrant single-cell phenotype with clinical implications

Multiple Myeloma (MM) is driven by clonal plasma cell (PC)-intrinsic factors and changes in the tumorigenic microenvironment (TME). To investigate if residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNAseq and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 18 healthy donors (HDs). Out of n=213,074 CD138pos PCs, 42,717 were genotypically identified as pPCs. Compared to HDs, we detected quantitative and qualitative differences in pPCs of patients showing immunoparesis, where we showed a pro-inflammatory status, driven by specific cellular interactions with TME. Finally, we derived a "hPC signature" that, once inferred in the CoMMpass dataset, was predictive of PFS and OS. Our findings show that genotypic, single-cell identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.

cancer biology↗

bioRxiv2023

DeltaF508-Cftr mutation in genetically diverse Collaborative Cross mice yields novel disease-relevant phenotypes for cystic fibrosis

Mutations of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) lead to Cystic Fibrosis (CF), but the substantial phenotypic variations are determined by non-CFTR allelic diversity. To map novel disease phenotypes in a CF mouse model, we used Collaborative Cross (CC) mice, a highly genetically diverse mouse resource population.{Delta} F508-Cftr homozygosity produced a fully penetrant lethal phenotype by eight weeks in two CC lines. The lethality of CC006{Delta}F508/{Delta}F508 was fully prenatal while CC037{Delta}F508/{Delta}F508 showed either prenatal or postnatal lethality. Novel phenotypes of CC037{Delta}F508/{Delta}F508 were revealed early in life including respiratory and systemic inflammatory profiles, and blood, bone marrow, pancreas, heart, and reproductive tract pathologies. Severe intestinal blockage was observed as common in other CF mouse models. These results suggest that the exploration of CF disease phenotypes in a mouse population with diverse genetic profiles is needed to map the genetic origin of currently unidentified disease traits and their potential translation to humans.

pathology↗

bioRxiv2022

7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability

Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and excitability. Genes related to neuronal transmission chiefly followed 7q11.23 dosage and appeared transcriptionally controlled, while translation and ribosomal protein genes followed the opposite trend and were post-transcriptionally buffered. Mechanistically, we uncovered REST regulon as a key mediator of observed phenotypes and rescued transcriptional and excitability alterations through REST inhibition. We identified downregulation of global protein synthesis, mGLUR5 and ERK-mTOR pathways activity in steady-state in both WBS and 7Dup, whereas BDNF stimulation rescued them specifically in 7Dup. Overall, we show that 7q11.23 CNVs alter protein synthesis and neuronal firing-established molecular and cellular phenotypes of neurodevelopmental disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/511483v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1b0fa99org.highwire.dtl.DTLVardef@146624org.highwire.dtl.DTLVardef@13dc89aorg.highwire.dtl.DTLVardef@13d098f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Long Noncoding RNA RROL Provides Chromatin Scaffold for MYC-WDR82 Interaction to Impact Lipid Metabolism and Tumor Cell Growth in Multiple Myeloma

Long noncoding RNAs (lncRNA) can drive the tumorigenesis and be susceptible to therapeutic intervention. To define the landscape of therapeutically actionable lncRNA dependencies in multiple myeloma (MM), we coupled our extensive lncRNA transcriptomic profile with lncRNA targeted CRISPR interference viability screen and identified RNA Regulator of Lipogenesis (RROL) as a leading lncRNA dependency in MM. RROL shares its origin with the microRNA locus MIR17HG, however supports the proliferation and survival of MM cells in a microRNA- and DROSHA- independent manner. We found that RROL provides a chromatin scaffold for the functional interaction between c-MYC and WDR82 to promote the regulation of the lipogenic pathways via the transcriptional control of the rate-limiting enzyme ACC1 in MM cells. Inhibition of RROL with clinically applicable antisense molecules disrupts its transcriptional and functional activities causing potent anti-tumor effects both in vitro and in vivo in two pre-clinical animal models. This study establishes lncRNA RROL as a therapeutically actionable dependency with a unique mechanism of action in support of myeloma cell growth.

cancer biology↗