Nuclear organization in cutaneous anaplastic large cell lymphomas
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Date
2022-08-15
Authors
Baslik, Ata
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Abstract
Genomes of eukaryotic cells are organized in 3D non-random multiscale structures that have significant effects on function of their genome, of the cell and collectively with other cells, function of the entire organism. Through deregulation of genome maintenance pathways, diseased cells become susceptible to accumulate mutations and can remodel the structure of their genome over time to ultimately gain phenotypes that advance their pathology. A state of high mutation rate is a hallmark of cancer called genomic instability. As an early disease feature that drives cancer evolution, genomic instability has been investigated in multiple settings. A driver of genomic instability is dysfunctional telomeres. These are repetitive DNA ‘TTAGGG’ sequences that protect chromosomal ends of healthy cells. Dysfunctional telomeres can fuse with other telomeres, in cancer, this causes events that results in broken and then rearranged chromosomes when cells attempt to divide with fused chromosomes. Telomere function requires interactions with multiple nuclear proteins that help maintain its structure and position; one such protein is lamin A/C. This protein plays key roles in genome organization and is part of a 3D protein structure called the nuclear lamina that envelopes the nucleus. Studies have identified remodelling of 3D telomere profiles and lamin A/C dysregulation in various cancers and they are found to be associated with lymphoid malignancies including Hodgkin’s Lymphoma, multiple myeloma, chronic lymphoid leukemia, and myelodysplastic syndromes. A disease where we so far lack understanding of genome remodelling and genome instability to the same extent as in the ones cited above is cutaneous anaplastic large cell lymphoma (C-ALCL), a lymphoid malignancy with relatively good prognosis. My project aimed to investigate changing 3D telomere profiles and lamin A/C expression in C-ALCL as it progressed through a malignant transformation. Results here show a heterogenous multifaceted telomere remodelling and lamin A/C deregulation associated with disease progression. Conclusions of this study offer an understanding of genomic alterations that drive transformation of a disease such as C-ALCL and serve as a building block to future studies that will help us understand what makes C-ALCL more treatable compared to other lymphoid malignancies.
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Keywords
Cellular Nuclear Organization, Lymphomas