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Single cell analysis of follicular lymphoma patient-derived xenograft in avian embryos

ABSTRACT: Single cell analysis of follicular lymphoma patient-derived xenograft in avian embryos

PROVIDER: PRJNA966204 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24412948_1.fastq.gz	Fastqsanger.gz
	SRR24412948_2.fastq.gz	Fastqsanger.gz
	SRR24412949_1.fastq.gz	Fastqsanger.gz
	SRR24412949_2.fastq.gz	Fastqsanger.gz
	SRR24412950_1.fastq.gz	Fastqsanger.gz

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Single cell analysis of follicular lymphoma patient-derived xenograft in avian embryos

Project description:Despite achieving high rates of complete remission with RCHOP immuno-chemotherapy, almost all patients with follicular lymphoma (FL) will experience multiple relapses after treatment. The understanding of the heterogeneity of treatment responses is limited by the absence of in vitro or in vivo experimental models. Here, we develop a primary FL cell xenograft model in chicken embryos to capture treatment response heterogeneity and analyze the mechanisms of response to immune-chemotherapy. Using light sheet microscopy, we observed that tumor volume reduction achieved with RCHOP treatment in ovo predicted progression free survival in multivariate analysis. To further explore the model, we used single-cell RNA sequencing to discover a signature of 21 genes upregulated after RCHOP exposure, with significant intratumoral heterogeneity. As a proof of concept, we functionally validated the involvement of BAX as a critical effector of RCHOP which can be targeted with venetoclax in vitro and in ovo.

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Project description:Nodal marginal zone lymphoma is a poorly defined entity in the WHO classification, largely based on criteria by exclusion and the diagnosis often remains subjective. Follicular Lymphoma lacking t(14;18), have similar characteristics which results in a major potential diagnostic overlap which this study aims to dissect. Four subgroups of lymphoma samples (n=56) were analyzed with high-resolution arrayCGH; Nodal marginal zone lymphoma, t(14;18)-negative Follicular Lymphoma, localized t(14:18)-positive Follicular Lymphoma and disseminated t(14;18)-positive Follicular Lymphoma. Gains on chromosomes 7, 8 and 12 were observed in all subgroups. The mean number of aberrations was higher in disseminated t(14;18)-positive Follicular Lymphoma compared to localized t(14:18)-positive Follicular Lymphoma (p<0.01) and the majority of alterations in localized t(14:18)-positive Follicular Lymphoma were also found in disseminated t(14;18)-positive Follicular Lymphoma. Nodal marginal zone lymphoma was marked by 3q gains with amplifications of four genes. A different overall pattern of aberrations was seen in t(14;18)-negative Follicular Lymphoma compared to t(14;18)-positive Follicular Lymphoma. t(14;18)-negative Follicular Lymphoma is marked by specific (focal) gains on chromosome 3 as observed in Nodal marginal zone lymphoma. Our results support the notion that localized t(14:18)-positive Follicular Lymphoma represents an early phase of disseminated t(14;18)-positive Follicular Lymphoma. t(14;18)-negative Follicular Lymphoma bears aberrations that are more alike Nodal marginal zone lymphoma, suggesting a relation between these groups.

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