Biology subjects

Breccia, M.

Publications and source records attributed to Breccia, M..

2 recordsLinked to original sources

bioRxiv2025

Phosphoproteomics reveals novel BCR::ABL1-independent mechanisms of resistance in chronic myeloid leukemia

BCR::ABL1 drives chronic myeloid leukemia (CML) disease and treatment, as revealed by the success of tyrosine kinase inhibitor (TKI) therapy. However, additional poorly characterized molecular pathways, acting as BCR::ABL1 independent mechanisms, play crucial roles in CML, contributing to leukemic stem cells (LSCs) persistence, TKI resistance and disease progression. Here, by combining high sensitive mass spectrometry (MS)-based phosphoproteomics with the SignalingProfiler pipeline, we obtained two signaling maps offering a comprehensive description of the BCR::ABL1 dependent and independent pro-survival signalling mechanisms. We leveraged these maps to unbiasedly and systematically discover therapeutic vulnerabilities, by implementing the Druggability Score computational algorithm. By this strategy, and in combination with in vitro and in ex vivo functional assays, we show a crucial role of acquired FLT3-dependency in resistant CML models. In conclusion, we reposition FLT3, one of the most frequently mutated drivers of acute leukemia, as a potential therapeutic target for TKI resistant CML patients.

systems biology↗

bioRxiv2023

Mecp2 knock-out astrocytes affect synaptogenesis by IL-6 dependent mechanisms

Synaptic abnormalities represent a hallmark for several neurological diseases and clarification of the underlying mechanisms constitutes a crucial step towards the development of therapeutic strategies. Rett syndrome (RTT) is a rare neurodevelopmental disorder, mainly affecting females, caused by heterozygous mutations in the X-linked Methyl-CpG-Binding Protein 2 (MECP2) gene, leading to a deep derangement of synaptic connectivity. Although initial studies have supported the exclusive involvement of neurons, recent data have highlighted the pivotal contribution of astrocytes in RTT pathogenesis through non-cell autonomous mechanisms. Since astrocytes regulate synaptogenesis by releasing multiple molecules, we investigated the influence of soluble factors secreted by Mecp2 KO astrocytes on synaptic density. We found that Mecp2 deficiency in astrocytes negatively affects their ability to support synapse formation by releasing synaptotoxic molecules, among which we identified interleukin-6 (IL-6). Notably, aberrant IL-6 expression exclusively emerges from a dysfunctional astrocyte-neuron crosstalk, and blocking IL-6 activity prevents synaptic alterations.

neuroscience↗