Project description:Anaplastic Large Cell Lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2-5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the Anaplastic Lymphoma Kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK(+) and ALK(-)ALCL subtypes, we performed a genome-wide DNA profiling using high density, single nucleotide polymorphism (SNP) arrays (SNP-array) on a series of 63 cases and seven cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK(-)ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an anti-apoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK(-)ALCL, and in 29% of all ALCL cases with a clinical implication. Genomic profiling of Anaplastic Large Cell Lymphoma
Project description:Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma that accounts for 10–15% of all childhood lymphomas. Despite the observation that more than 90% of the cases show ALK-rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insight into the molecular heterogeneity within ALK-positive ALCL, we analyzed 46 ALK-positive ALCL samples by whole-exome sequencing, RNA-sequencing, and DNA methylation array analysis. Gene expression and methylation profiling consistently subclassified ALK-positive ALCL cases into two groups differentiated by ALK expression level. The ALK-low group showed enrichment pathways of the immune response and cytokine signaling and were more heavily hypermethylated than the ALK high group, which was characterized by enriched pathways of cell growth, proliferation, metabolic pathways, and large copy number change. Taken together, these findings suggest that there is molecular heterogeneity within pediatric ALK+ALCL, predicting distinct biological mechanisms that may be utilized as prognostic markers.
Project description:Overlap Between Pediatric Nodal Marginal Zone Lymphoma (PNMZL) and Pediatric-Type Follicular Lymphoma (PTFL) : Morphological and Molecular Analysis
Project description:Emerging evidence shows that small extracellular vesicles (S-EVs) play a critical role in cancer biology. However, the role of S-EVs in pediatric anaplastic large cell lymphoma (ALCL) is still largely unknown. Small RNA sequencing of plasma S-EVs revealed a peculiar microRNA profile in pediatric ALCL patients compared to healthy donors (HD). In particular, the liver-specific miR-122-5p was more abundant in ALCL plasma S-EVs compared to HD. Elevated levels of miR-122-5p correlated with advanced stage disease and impaired hepatic function in ALCL patients. In vitro experiments demonstrated that miR-122-5p inhibits glucose consumption in stromal cells, and the increased glucose availability enhances ALCL cell aggressiveness. Moreover, miR-122-5p promoted tumor dissemination in vivo. This study identified a new molecular factor promoting ALCL cell dissemination. This finding sets the ground for investigating the clinical use of miR-122-5p antagonists in ALCL patients to potentially improve the clinical outcome.
Project description:Anaplastic Large Cell Lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2-5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the Anaplastic Lymphoma Kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK(+) and ALK(-)ALCL subtypes, we performed a genome-wide DNA profiling using high density, single nucleotide polymorphism (SNP) arrays (SNP-array) on a series of 63 cases and seven cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK(-)ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an anti-apoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK(-)ALCL, and in 29% of all ALCL cases with a clinical implication.
Project description:Overlap Between Pediatric Nodal Marginal Zone Lymphoma (PNMZL) and Pediatric-Type Follicular Lymphoma (PTFL) : Morphological and Molecular Analysis (OncoScan)
Project description:Overlap Between Pediatric Nodal Marginal Zone Lymphoma (PNMZL) and Pediatric-Type Follicular Lymphoma (PTFL) : Morphological and Molecular Analysis (CytoScan)
Project description:miRNA profiling has been performed on primary tumor samples collected at diagnosis from pediatric patients affected by T-cell lymphoblastic lymphoma.
Project description:Emerging evidence indicates that extracellular vesicles, particularly exosomes, play a role in several biological processes and actively contribute to cancer development and progression, by carrying and delivering proteins, transcripts and small RNAs (sRNAs). We profiled by RNA-seq the sRNA content of circulating exosomes of 20 pediatric patients with Anaplastic Large Cell Lymphoma (ALCL), 5 healthy controls and of 5 ALCL cell lines. Our analysis disclosed that non-miRNA derived sRNAs constitute the prominent fraction of sRNA loaded in exosomes. A fragment of RNY4 was the most abundant of 180 sRNAs significantly enriched in exosomes of ALCL patients compared to controls. Further investigation by qRT-PCR of RNY4 fragments and full-length sequence disclosed that the latter is massively loaded into exosomes of ALCL patients with more advanced and aggressive disease. Since recent findings supported a role of RNY4 in the modulation of tumor microenvironment, our data open new possibilities to understand how tumor derived exosomes can facilitate disease spread in ALCL patients.