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Beclin-1 is dispensable for chromosome congression and proper outer kinetochore assembly

ABSTRACT: Chromosomal instability (CIN) is defined by the propensity to acquire structural and/or numerical aberration in the normal cellular karyotype and is often associated with cancer. Autophagy is a catabolic process that leads to the recycling of cellular components that may positively or negatively impact on cancer development and progression, depending on the context. Recent work postulated that the depletion of the pro-autophagic and tumor suppressive protein Beclin 1 triggers CIN by interfering with mitotic chromosome segregation, providing a possible mechanism for how Beclin 1 can act as a tumor suppressor (Fremont et al., PMID: 23478334). Here, we present data supporting the notion that the phenotypes described in Fremont et al., depend on a siRNA off-target effect. The transcriptomic analysis shown here was designed to identify the factor(s) that are responsible for such phenotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE69052 | GEO | 2015/09/02

SECONDARY ACCESSION(S): PRJNA284409

REPOSITORIES: GEO

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Project description:Chromosomal instability (CIN), defined as an increased occurrence of chromosome segregation errors during cell division, is a prominent form of genomic instability (Bakhoum and Avi Landau, 2017). It is the major cause of aneuploidy, an imbalanced complement of whole chromosomes or chromosome arms, which is the most prevalent genetic alteration in human cancers (Vasudevan et al., 2021; Santaguida and Amon, 2015). Importantly, aneuploidy is commonly associated with ongoing CIN through consecutive cell divisions (Shelzer et al. 2011; Passerini et al., 2016), resulting in intratumor genetic heterogeneity, a central driver of cancer evolution and therapeutic resistance (Sansregret et al., 2018; Ben-David and Amon, 2019). Indeed, aneuploidy has been shown to act both as a tumor suppressor and as a tumor initiator (Weaver et al., 2007; Silk et al., 2013; Vasudevan et al., 2020), most likely depending on the specific chromosomes that are gained or lost (Ben-David et al., 2011; Sack et al., 2018; Adell et al., 2023). Despite the ubiquitous presence of CIN in several aneuploid cancer types and its clinical relevance, its presence in B-cell acute lymphoblastic leukemia (B-ALL) remains largely unexplored owing to the impaired proliferation of leukemic cells in vitro and the lack of reliable experimental models to comprehensively assess chromosome segregation in vivo. B-ALL is the most frequent childhood cancer, with 75% of cases occurring in children under 6 years of age, and it is characterized by the accumulation of highly proliferative immature B-cell precursors in the bone marrow (BM) (Hunger and Mullighan, 2015). The presence of CIN and its contribution to aneuploid cB-ALL progression is largely unknown due to the lack of preclinical models to study actively dividing cells. Accordingly, studies of CIN in cB-ALL are limited to the characterization of chromosomal copy-number heterogeneity (chr-CNH) in primary cB-ALL samples, but there is controversy over its presence due to the different techniques used to assess karyotype variability (Raimondi et al., 1996; Talamo et al., 2010; Alpar et al., 2014; Heerema et al.; 2007; Ramos-Muntada et al., 2022). Here, we explored the presence and the levels of CIN in different clinically-relevant aneuploid subtypes of cB-ALL using single-cell whole-genome sequencing (WGS) of primary samples to reliably assess chr-CNH, and by generating a large cohort of PDX models from primary cB-ALL samples (cB-ALL-PDX). Our results in cB-ALL-PDX models revealed variable levels of CIN in aneuploid cB-ALL subtypes, which significantly correlate with intraclonal karyotype heterogeneity and with disease progression. Additionally, mass-spectrometry analyses of cB-ALL-PDX samples revealed a CIN “signature” enriched in mitosis and chromosome segregation regulatory pathways. We speculate that this signature identifies adaptive mechanisms to ongoing CIN in aneuploid cB-ALL cells, which displayed a transcriptional signature characterized by an impaired mitotic spindle as observed by RNA-sequencing (RNA-Seq) analyses of a large cohort of primary cB-ALL patient samples. Our work might help to improve stratification of patients with cB-ALL with different levels of CIN who could benefit in the future from new therapeutic approaches aiming to target ongoing CIN.

Project description:The core component of the class III phosphatidylinositol 3-kinase complex, Beclin 1, takes part in different protein networks, thus switching its role from inducing autophagy to regulating autophagosomal maturation and endosomal trafficking. While assessed in neurons, astrocytes and microglia, its role was far less investigated in myelinating glia, including Schwann cells (SCs), responsible for peripheral nerve myelination. Remarkably, the dysregulation in endosomal trafficking is emerging as a pathophysiological mechanism underlying peripheral neuropathies, such as demyelinating Charcot-Marie-Tooth diseases. By knocking out Beclin 1 in SCs we here generated a novel mouse model (Becn1 cKO), developing a severe and progressive neuropathy, accompanied by involuntary tremors, body weight loss and premature death. Ultrastructural analysis revealed abated myelination and SCs displaying enlarged cytoplasm with progressive accumulation of intracellular vesicles. Transcriptomic and histological analysis from sciatic nerves of 10-day and 2-month-old mice revealed pro-mitotic gene deregulation and increased SCs proliferation at both stages with axonal loss and increased immune infiltration in adults, well reflecting the progressive motor and sensory functional impairment that characterizes Becn1 cKO mice, compared to controls. Our study establishes a further step in understanding key mechanisms in SC development and points to Beclin 1 and its regulated pathways as targets for demyelinating CMT forms. A novel conditional gene knockout was generated to investigate the role that Beclin 1 exerts in Schwann cells and in myelination. The newly generated mouse line resulted in a model for severe and progressive peripheral neuropathy. Together with defective myelination, we described radial sorting defects, motor and sensory neuron impairments, immune infiltrate in adults and a huge transcripts deregulation. The emerged deregulated signalling pathways highlighted how Beclin 1 is able to coordinate integrated signaling pathways essential for Schwann cell maturation and nerve development and homeostasis.

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Beclin-1 is dispensable for chromosome congression and proper outer kinetochore assembly

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