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Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice

ABSTRACT: Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small animal models. Here we demonstrate that IL-15 is a critical CTCL growth and survival factor. Importantly, a genetically engineered immunodeficient mouse model expressing human IL-15 uniquely supported the growth of patient derived Sezary cells relative to conventional immunodeficient mouse strains. Patient derived xenograft (PDX) SS models recapacitated the pathologic features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single cell transcriptome analysis revealed tissue specific regulation of gene expression and distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of the humanized IL-15, immunodeficient mice for SS PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact.

ORGANISM(S): Mus musculus

PROVIDER: GSE227326 | GEO | 2023/09/29

REPOSITORIES: GEO

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Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice [scRNA/TCR-seq]

Project description:Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small animal models. Here we demonstrate that IL-15 is a critical CTCL growth and survival factor. Importantly, a genetically engineered immunodeficient mouse model expressing human IL-15 uniquely supported the growth of patient derived Sezary cells relative to conventional immunodeficient mouse strains. Patient derived xenograft (PDX) SS models recapacitated the pathologic features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single cell transcriptome analysis revealed tissue specific regulation of gene expression and distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of the humanized IL-15, immunodeficient mice for SS PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact.

2023-09-29 | GSE229406 | GEO

Transcription profiling of Hut 78 cells (Sezary sndrome) with a stable knockdown of AHI-1 expression to identify mediators of the AHI-1.

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Identification of HCK and BIN1 as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells

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CD164 and FCRL3 are highly expressed on CD4+CD26- T cells in Sezary syndrome; inverse correlation between CD164 and CD26 expression

Project description:Sezary syndrome (SS) represents a leukemic variant of cutaneous T cell lymphoma (CTCL) with circulating malignant CD4 T cells trafficking to the skin. The cell surface molecules present on malignant cells are also expressed on normal CD4 T cells. Therefore, we attempted to find a specific marker for malignant cells that would distinguish them from normal cells. Comprehensive microarray analysis of gene expression in the malignant cells indicated significantly increased levels of mRNA for cell surface markers CD164, a sialomucin found on human CD34+ hematopoietic stem cells, as well as FCRL3, a molecule present on a subset of human natural T regulatory cells. Both markers were increased in CD4 T cells from the SS patients compared to those from Mycosis Fungoides patients and healthy volunteers. Subsequent studies utilizing QPCR and flow cytometry confirmed the increased expression of CD164 and FCRL3 mainly in CD4+CD26- T cells of SS patients. Our results suggest that CD164 can serve as a marker for diagnosis as well as disease monitoring of CTCL/SS, whereas the FCRL3 expression correlates with disease progression.

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HDAC Inhibitors Impair GATA-3 DNA Binding and Target Gene Expression in T-cell Neoplasms

Project description:To investigate early transcriptional changes upon HDACi treatment, a well characterized and p53-deficient CTCL cell line (H9) and primary malignant T cells isolated from the peripheral blood of Sezary Syndrome (SS) patients (n=3) were cultured for 6 hours in the presence of vehicle control, romidepsin (romi) or belinostat (beli) and transcriptionally profiled by RNA-seq

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Project description:Sezary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course. The goal of our study is to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sezary cels, fourteen of them fulfilling the diagnostic criteria of SS. Peripheral blood samples were collected for each patient and CD4+ T-lymphocytes and Granulocytes were isolated. DNA and RNA was extracted for matched normal and tumor materials. Whole exome sequencing was performed on matched normal and tumor tissues of 12 patients and RNA sequencing was performed on 10 patients. For 7 of these patients, we have both exome as well as RNA sequencing data. In this study, we present a complex genomic landscape of Sezary syndrome with several point mutations, copy number variations and fusion events which could contribute to the pathogenesis of SS.

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Identification of p38 beta as a therapeutic target for the treatment of Sézary Syndrome

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The Mutational Landscape of CTCL and Sezary Syndrome.

Project description:<p>Sezary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4+ T cells. To identify new genetic alterations involved in Sezary syndrome and CTCL transformation we performed whole-exome sequencing of tumor-normal sample pairs from 26 Sezary syndrome and 16 CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sezary syndrome including highly prevalent recurrent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A, and CDKN1B tumor suppressor genes. Mutation analysis identified a broad spectrum of somatic mutations involving key genes involved in epigenetic regulation (TET2, CREBBP, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including mutations in MAPK1, BRAF, CARD11 and PRKG1 driving increased MAPK, NFKB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sezary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.</p>

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Comprehensive transcriptional and clonotypic analysis of peripheral blood constituents in Sézary syndrome.

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