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

ABSTRACT: Although central to the diagnosis of cutaneous T cell lymphoma (CTCL) is the malignant clonal proliferation of skin-tropic T cells the diagnosis represents a spectrum of diseases and clinical courses. Most patients have an indolent disease course with cycling of therapies, while others, especially in advanced stages of disease, have aggressive progression and poor median survival. Adding to the difficulty of treatment, Sézary syndrome (SS), a leukemic variant of CTCL, lacks highly characteristic phenotypic and genetic markers that would aid in not only the diagnosis of the malignancy, but also response to therapies. Using single-cell mRNA and T-cell-receptor sequencing, of peripheral blood immune cells in SS, we extensively mapped the transcriptomic variations of nearly 50,000 T cells of both malignant and nonmalignant origins. We identified potential diverging SS cell populations, including quiescent and proliferative populations shared across multiple patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146586 | GEO | 2022/03/04

REPOSITORIES: GEO

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Project description:Suberoyl Anilide Hydroxamic Acid (SAHA), also named under Vorinostat, is an inhibitor of class I and II histone deacetylases (HDACi) approved by the USA Food and Drug Administration (FDA) for the treatment of advanced and refractory cutaneous T-cell lymphomas (CTCL). Its limited efficacy led to its use in various combination therapies. Given that SAHA modifies the expression of many genes under control of Sp1 (or Sp3) transcription factors, we investigated here its association to the FDA-approved anticancer antibiotic Mithramycin (MitA), a direct inhibitor of the binding of Sp1 family factors to GC-rich DNA promoters. We found that MitA alone, similar to SAHA, efficiently induced the apoptotic death of peripheral blood lymphocytes from Sézary syndrome (SS) patients while the two drugs in combination demonstrated a synergistic effect that could even overcome the resistance to MitA used in mono-treatment. A deep analysis of gene expression profiling suggested that SAHA and MitA, either independently or synergistically, counteracted many intertwined pro-survival pathways mis-regulated in SS cells as TCR, Notch1, mTOR, PI3K/Akt, JAK/STAT and b-catenin pathways, as well as the resistance of these tumors to intrinsic and extrinsic apoptosis. This analysis also suggested that SAHA/MitA combined treatment might efficiently oppose to the abnormal adhesion, migration and invasive properties of SS cells, in addition their immunosuppressive behavior. Finally, from a mechanistic point of view, our observations strongly support a major role of additive or synergistic epigenetic modifications in the combined effect of the two drugs, with a rather limited contribution of Sp1 (or Sp3)-mediated transcriptional regulation. Peripheral blood tumor cells from Sézary patients were expanded in vitro and treated with SAHA and/or MitA previous to RNA isolation and Microarray processing. Deep analysis of gene expression profiling suggested that SAHA and Mithramycin A (MitA), either independently or synergistically, counteracted many interwined pro-survival pathways mis-regulated in Sézary cells, as well as abnormal adhesion, invasion and invasive properties. Data also favored additive or synergistic epigenetic modifications in the combined effect of the two drugs.

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

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