Graduation Year

2022

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

José R. Conejo-Garcia, Ph.D.

Committee Member

John Cleveland, Ph.D.

Committee Member

Kenneth Wright, Ph.D.

Committee Member

Javier Pinilla-Ibarz, M.D., Ph.D.

Committee Member

Lubomir Sokol, M.D., Ph.D.

Committee Member

Owen O’ Connor, M.D., Ph.D.

Keywords

Cancer, Mycosis Fungoides, SATB1, Sezary Syndrome, TCR

Abstract

The pathogenesis of Cutaneous T cell lymphoma (CTCL) remains unclear. Using conditional knockout mice, we found that ablation of the genomic organizer Special AT-rich sequence-binding protein-1 (Satb1) caused malignant transformation of mature, skin-homing, Notch-activated CD4+ and CD8+ T cells into progressively fatal lymphoma. Mechanistically, Satb1 restrained Stat5 phosphorylation and the expression of skin-homing chemokine receptors in mature T cells. H3K27 and H3K9 trimethylation occluded the SATB1 promoter in Sézary cells, while inhibition of SUV39H1/2 methyltransferases (unlike EZH2 inhibition), restored protective SATB1 expression and selectively abrogated the growth of primary Sézary cells more effectively than romidepsin. Additionally, using single-cell RNA/TCR sequencing of 106,130 CD3+CD4+, CD26-/CD7- malignant lymphocytes from the peripheral blood of 7 patients with CTCL, coupled to single-cell ATAC-seq of 35,857 CTCL cells, we show that tumor-initiating cells in Sézary syndrome and Mycosis fungoides (MF) exhibit different trajectories of differentiation. Sézary cells exhibit narrower repertoires of TCRs, compared to MF, which are maintained throughout malignant cell expansion, while differentiated MF cells exhibit clonal enrichment. Surprising, we identified ≥200 mutations in hematopoietic stem cells from Sézary syndrome patients. Mutations in key oncodrivers were also present in peripheral Sézary cells, which showed the hallmarks of recent thymic egression. However, Sézary cells expand independently of antigen recognition, while mutations in non-malignant cells suggest that they complete their malignant transformation in the periphery. Therefore, CTCL arises from mutated lymphocyte progenitors that acquire TCRs in the thymus.

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