Graduation Year
2024
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Molecular Biosciences
Major Professor
Eric Padron, M.D.
Co-Major Professor
Robert Deschenes, Ph.D.
Committee Member
Florian Karreth, Ph.D.
Committee Member
Hana Totary-Jain, Ph.D.
Committee Member
Niketa Patel, Ph.D.
Committee Member
Subhra Mohapatra, Ph.D.
Keywords
Inflammation, myeloproliferation, Interleukin 6, Leukemia, Clonal Hematopoiesis
Abstract
TET2 is a dioxygenase that regulates gene expression and hematopoiesis by oxidizing 5-methylcytosine residues on DNA to 5-hydroxymethylcytosine. TET2 mutations are common genetic events in hematological disorders. For example, TET2 is the most frequently mutated gene in Chronic Myelomonocytic Leukemia and occurs in about 33% of other myeloid malignancies. It is also the second commonest mutation in clonal hematopoiesis of indeterminate potential (CHIP), a common premalignant condition in the elderly. TET2 mutations arise in founding clones and are implicated in many non-hematological sequelae seen in CHIP like atherosclerotic disease, chronic liver disease, and severe microbial infections.
The development of TET2-deficient hematological disorders as well as their sequelae is associated with the potentiation of inflammatory circuits. However, while multiple studies show the response of Tet2-deficient cells to heightened inflammation, the major downstream effector responsible for potentiating this oncogenic inflammation is unknown.
To address this, we used scRNA and scATAC-seq in COVID-19 patients with and without TET2 mutations reasoning that inflammation from COVID-19 may unmask downstream targets of TET2 mutations. Using this approach, we identified MALAT1, a druggable lncRNA, as a central downstream effector of TET2 mutations that is both necessary and sufficient to induce inflammatory Tet2-deficient phenotypes. We also show TET2 deficiency increases MALAT1 expression by reducing chromatin accessibility of EGR1. Finally, we describe a “shielding” interaction between MALAT1 and P65 leading to reduced PP2A dephosphorylation, thus preventing resolution of inflammatory signaling and promoting the development of Tet2-deficient phenotypes. This work nominates MALAT1 as a viable therapeutic target in TET2-mutated disorders.
Scholar Commons Citation
Ben-Crentsil, Nana Adjoa, "MALAT1 Mediates TET2 Loss of Function-Driven Oncogenic Inflammation Via RNA Shielding of NF- Kappa B P65" (2024). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/10597
