Biology subjects

Bresolin, S.

Publications and source records attributed to Bresolin, S..

5 recordsLinked to original sources

bioRxiv2026

Single-cell multiomic profiling reveals lineage plasticity in pediatric B-lineage Acute Lymphoblastic Leukemia during the early phase of treatment

The biological bases of transient myelomonocytic switch (mmSW) during induction therapy in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains largely undefined. Here we integrated single-cell transcriptomic and surface marker profiling with genomic and DNA methylation analyses of pediatric BCP-ALLs, including matched diagnosis (Dx) and Day+15 samples from mmSW-positive (mmSWpos) and mmSW-negative cases. At Dx, mmSWpos leukemia samples were enriched for hematopoietic stem/progenitor-like cell subpopulations. Trajectory and entropy analyses identified a pre-existing "fate-uncertain" cell compartment co-expressing both lymphoid and myeloid programs. Longitudinal single-cell data showed that, in mmSWpos samples, this population undergoes complete transdifferentiation. mmSWpos are enriched for Ras pathway and chromatin regulation mutations and display a specific DNA hypermethylation pattern at Dx. These findings indicate that transient mmSW arises from intrinsic leukemic plasticity, in which immature transcriptomic and distinct epigenetic states at diagnosis enable lineage switching under the pressure of ALL treatment.

Cancer Biology↗

bioRxiv2025

Leukemic Cells Manipulate MSCs Bioelectrical Signals to Reshape the Bone Marrow Niche

Mesenchymal stromal cells (MSCs) are key components of the tumor microenvironment (TME), influencing leukemia progression through poorly understood mechanisms. We investigated the bioelectrical properties of MSCs derived from pediatric AML patients (AML-MSCs) and identified a significant depolarization of their resting membrane potential (Vmem, -14.7mV) compared to healthy MSCs (h-MSCs, -28.5mV), accompanied by downregulation of CaV1.2 L-type calcium channel expression. AML-MSCs displayed increased spontaneous calcium oscillations, suggesting altered ion homeostasis. Notably, h-MSCs exposed to AML blasts underwent a similar Vmem depolarization (-11.8mV) and CaV1.2 downregulation, indicating that leukemic cells actively reprogram MSCs. Functionally, Vmem depolarization in h-MSCs promoted a pro-leukemic phenotype, whereas hyperpolarization of AML-MSCs restored a normal behavior. CaV1.2 over-expression by lentiviral vectors in AML-MSCs shifted Vmem toward hyperpolarization and partially reversed their leukemia-supportive properties, in part through CaV1.2 transfer via tunneling nanotubes. These findings reveal that AML blasts impose a bioelectrical signature on MSCs, modulating ion channel activity to sustain a leukemic niche. Targeting this electrical reprogramming through CaV1.2 restoration represents a potential strategy to re-establish homeostasis in the bone marrow microenvironment.

cancer biology↗

bioRxiv2021

CRAFT: a bioinformatics software for custom prediction of circular RNA functions

Circular RNAs (circRNAs), transcripts generated by backsplicing, are particularly stable and pleiotropic molecules, whose dysregulation drives human diseases and cancer by modulating gene expression and signaling pathways. CircRNAs can regulate cellular processes by different mechanisms, including interaction with microRNAs (miRNAs) and RNA-binding proteins (RBP), and encoding specific peptides. The prediction of circRNA functions is instrumental to interpret their impact in diseases, and to prioritize circRNAs for functional investigation. Currently, circRNA functional predictions are provided by web databases that do not allow custom analyses, while self-standing circRNA prediction tools are mostly limited to predict only one type of function, mainly focusing on the miRNA sponge activity of circRNAs. To solve these issues, we developed CRAFT (CircRNA Function prediction Tool), a freely available computational pipeline that predicts circRNA sequence and molecular interactions with miRNAs and RBP, along with their coding potential. Analysis of a set of circRNAs with known functions has been used to appraise CRAFT predictions and to optimize its setting. CRAFT provides a comprehensive graphical visualization of the results, links to several knowledge databases, and extensive functional enrichment analysis. Moreover, it originally combines the predictions for different circRNAs. CRAFT is a useful tool to help the user explore the potential regulatory networks involving the circRNAs of interest and generate hypotheses about the cooperation of circRNAs into the modulation of biological processes. Key pointsO_LICRAFT is a self standing tool for comprehensive circRNA function prediction. C_LIO_LICRAFT functions include circRNA sequence reconstruction, microRNA and RNA-binding protein response elements and coding potential prediction. C_LIO_LIPredictions for multiple circRNAs are connected to infer possible cooperation networks and illustrate the potential impact of circRNAs on biological and disease processes. C_LI

bioinformatics↗

bioRxiv2018

Simultaneous B and T cell acute lymphoblastic leukemias in zebrafish driven by transgenic MYC: implications for oncogenesis and lymphopoiesis

Precursor-B cell acute lymphoblastic leukemia (pre-B ALL) is the most common pediatric cancer, but there are no useful zebrafish pre-B ALL models. We describe the first highly-penetrant zebrafish pre-B ALL, driven by human MYC. Leukemias express B lymphoblast-specific genes and are distinct from T cell ALL (T-ALL)--which these fish also develop. Zebrafish pre-B ALL shares in vivo features and expression profiles with human pre-B ALL, and these profiles differ from zebrafish T-ALL or normal B and T cells. These animals also exhibit aberrant lymphocyte development. As the only robust zebrafish pre-B ALL model and only example where T-ALL also develops, this model can reveal differences between MYC-driven pre-B vs. T-ALL and be exploited to discover novel pre-B ALL therapies.\n\nStatement of significanceWe describe the first robust zebrafish pre-B ALL model in MYC-transgenic animals known to develop T-ALL, revealing the only animal model with both human ALL types. We also describe aberrant multi-lineage lymphopoiesis. This powerful system can be used to study MYC-driven leukemogenesis and discover new pre-B ALL targeted therapies.

cancer biology↗

bioRxiv2018

USP7 cooperates with NOTCH1 to drive the oncogenic transcriptionalprogram in T cell leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Treatments1-6 show high response rates but have debilitating effects and carry risk of relapse5,7,8. Previous work implicated NOTCH1 and other oncogenes1,2,9-20. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Here, we demonstrate that ubiquitin-specific protease 7 (USP7)21-32 controls leukemia growth by stabilizing the levels of the NOTCH1 and JMJD3 demethylase. USP7 is overexpressed T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 through deubiquitination. USP7 is bound to oncogenic targets and controls gene expression through H2B ubiquitination and H3K27me3 changes via stabilization of NOTCH1 and JMJD3. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and USP7 inhibition alters associated gene activity. These results provide a new model for deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. USP7 inhibition33 significantly blocked T-ALL cell growth in vitro and in vivo. Our studies also show that USP7 is upregulated in the aggressive high-risk cases of T-ALL and suggest that USP7 expression might be a prognostic marker in ALL and its inhibition could be a therapeutic tool against aggressive leukemia.

cancer biology↗