Biology subjects

Maletzki, C.

Publications and source records attributed to Maletzki, C..

3 recordsLinked to original sources

bioRxiv2026

mRNA deep sequencing profiling and integrative miRNA-mRNA network analysis in pediatric Burkitt leukemia and lymphoma

Background: Although the genomic alterations in Burkitt leukemia and lymphoma (BL) have been extensively studied, data on genome-wide dysregulation of messenger RNA (mRNA) and microRNA (miRNA) in Burkitt leukemia (BuAL) and Burkitt lymphoma (BuLY) are scarce. The aim of this study was to analyze mRNA and miRNA expression profiles in pediatric BuAL/BuLY to identify dysregulated mRNA-miRNA networks. Methods: Total RNA from fresh tumor samples of 13 pediatric BL patients (BuAL n=7, BuLY n=6) and 4 pediatric normal control lymphoid tissue (NCLT) samples was included for mRNA-deep sequencing and miRNA-microarrays studies. Differential expression (DE) analysis of mRNAs and miRNAs as well as gene set and functional enrichment analysis were performed. The multiMiR R package was used to identify the validated target genes for the dysregulated miRNAs. miRNA-mRNA target interaction analysis was performed combining DE, validated targets observed among the inverse-significant miRNA-mRNA correlations, with evidence statistics retained (p[≤]-0.5 and Benjamini-Hochberg (BH) -adjusted correlation p-value< 0.05). Results: BL showed 1965 DE genes (DEG) compared to NCLT (1214 upregulated, 751 downregulated) (p-adj<0.05, log2FC>0.5) and 11 DE miRNAs (three upregulated and eight downregulated) (FC>1.5, p-adj<0.05). The transcriptional differences observed between BL and normal lymphoid tissue inferred by functional enrichment analysis identified along a MYC-driven proliferative backbone with strong E2F4 and MYB pathway activity, activation of the MAPK, PI3K and the G2/M checkpoint signaling pathways and repression of the JAK-STAT, NFkB, TP53, TRAIL and hypoxia pathways (p-adj<0.05). Functional enrichment analysis highlighted an upregulation of proliferative and metabolic pathways accompanied by an attenuated inflammatory and immunosurveillance signaling in BL compared to NCLT. Correlated miRNA-mRNA expression analysis identified DE dysregulated miRNAs and their validated target genes. DE downregulated miRNAs (hsa-miR-150-5p, hsa-miR-342-3p and hsa-miR-450-5p, among others) inversely correlated with upregulated mRNA targets showing pathway enrichment related to transcriptional activity and nuclear organization modules. mRNA targets of DE upregulated miRNAs (hsa-miR-106a-5p, hsa-miR-17-5p and hsa-miR-7-5p) were enriched in downregulated pathways related to immune response processes. Conclusions: Overall, this pilot study provides new insights on key proliferative, metabolic and cytokine-mediated immune signaling pathways in BL and highlights miRNA-mRNA networks influencing transcriptional activity and immune surveillance, paving the way for experimental validation models.

cancer biology↗

bioRxiv2023

Molecular Determinants of Calcitriol Signaling and Sensitivity in Glioma Stem-like Cells

Glioblastoma is the most common primary brain cancer in adults and represents one of the worst cancer diagnosis for the patients. Suffering from a poor prognosis and limited treatment options, tumor recurrences are virtually inevitable. Additionally, treatment resistance is very common for this disease and worsens the prognosis. These and others factors are hypothesized to be largely due to the fact that glioblastoma cells are known to be able to obtain stem-like traits and thereby driving these phenotypes. Recently, we could show that the in vitro and ex vivo treatment of glioblastoma stem-like cells with the hormonally active form of Vitamin D3, Calcitriol (1,25(OH)2-vitamin D3) can block stemness in a subset of cell lines and reduce tumor growth. Here, we expanded our cell panel to over 40 different cultures and can show that, while half of the tested cell lines are sensitive, a quarter can be classified as high-responders. Using genetic and proteomic analysis, we further determined that treatment success can be partially explained by specific polymorphism of the Vitamin D3 receptor and that high-responders display a proteome suggestive of blockade of stemness, as well as migratory potential.

cancer biology↗

bioRxiv2019

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1-/- mice

MLH1 knock out mice represent a preclinical model that resembles features of the human counterpart. As these mice develop mismatch repair deficient (MMR-D) neoplasias in a sequential twin-peaked manner (first lymphomas, then gastrointestinal tumors) we aimed at identification of the underlying molecular mechanisms. Using whole-exome sequencing, we focused on (I) shared and (II) mutually exclusive mutations and described the processes of ongoing mutational events in tumor-derived cultures.\n\nA heterogeneous genetic landscape was found, with few mutations shared among different neoplasias (ARID1A and IDH2). Mutations in tumor suppressor genes SMAD4 and POLE were mutually exclusive in lymphomas, most likely contributing to a more aggressive in vivo phenotype. Comparing the mutational profile of selected primary tumors and their corresponding cell line upon in vitro culture revealed continuous increased numbers of somatic gene mutations. The same was true for coding microsatellite mutations in selected MMR-D target genes, showing a gradual increase during in vitro passage. With respect to this latter type of mutations, partial overlap was detectable, yet recognizing shared vaccination antigens. The two most promising candidates are AKT3, a RAC-gamma serine/threonine-protein kinase with relevance in maintenance of cellular homeostasis and the endonuclease ERCC5 (Excision Repair 5), involved in DNA excision repair.\n\nNovel results of a comparison between spontaneously developing lymphomas and gastrointestinal tumors as models for MMR-D driven tumorigenesis are reported. In addition to identification of ARID1A as a potentially causative mutation hotspot, our comprehensive characterization of the mutational signature is a starting point for immune-based approaches to therapy.\n\nAuthor SummaryThis study describes the mutational spectrum of MLH1-/--associated tumors, spontaneously developing in mice. While these tumors arise at the bottom of the same germline mutation, the clinical presentations as well as resulting molecular alterations are heterogeneous, and thus likely being directly linked. Highly aggressive lymphomas, developing early in life are ultra-hypermutated and harbor mutations in tumor suppressor genes SMAD4 and POLE. Gastrointestinal tumors develop later in life and show different mutations. By performing in-depth whole exome sequencing analysis, we here identified for the first time a common mutational hotspot. ARID1A constitutes a potentially causative mutation, shared among different MLH1-/--associated tumors and thus irrespective of the origin. Additional interesting and identified candidate genes include AKT3, a RAC-gamma serine/threonine-protein kinase and the endonuclease ERCC5. Both genes are bona fide tumor suppressors with significant relevance in DNA excision repair and maintenance of cellular homeostasis. This finding is of particular relevance for subsequent therapeutic and - even more important - prophylactic vaccination approaches aiming at entity-overlapping treatment of MLH1-/--related tumors.

cancer biology↗