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48006.pdf (1000.01 KB)
ETD Abstract Container
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Investigating co-mutational synergy in TET2 mutant leukemic transformation.
Author Info
Raval, Jahnavi
ORCID® Identifier
http://orcid.org/0009-0007-4852-2253
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712914392187043
Abstract Details
Year and Degree
2024, MS, University of Cincinnati, Medicine: Cancer and Cell Biology.
Abstract
Acute myeloid leukemia (AML) is a rare hematological malignancy characterized by genetic and epigenetic aberrations in hematopoietic progenitor/stem cells (HPSCs). Molecular profiling studies of AML patients have suggested a sequential acquisition of co-occurring mutations during leukemogenesis, with mutations in epigenetic regulatory genes like TET2 and DNMT3A often serving as the initiating events due to their high variant allele frequencies (VAF). Moreover, these initiating mutations exhibit a key role in clonal hematopoiesis (CH), a state marked by the expansion of dominant mutant HPSC clones without evident disease. Concurrent mutations, notably in genes such as NPM1, NRAS, and FLT3, are known to co-occur with epigenetic modifier mutations and are believed to manifest within a pre-existing mutant clone. While targeted therapies have been established for specific AML mutations like FLT3 and IDH1/2, treating patients lacking these mutations or those who develop resistance remains a critical challenge. Recent strides in single-cell sequencing have revolutionized our comprehension of AML pathogenesis by unveiling the clonal architecture and mutation order, which is not possible through bulk sequencing approaches. Leveraging technologies such as single-cell targeted DNA sequencing, we and others have dissected genetic variations at the single-cell level, unraveling how specific combinations of mutations, such as TET2/NPM1, can synergistically propel leukemogenesis, resulting in the amplification of double mutant clones compared to single mutant clones. Furthermore, single-cell multi-omics investigations have delineated that the co-mutational context exerts a profound impact on the differentiation and immunophenotype of transformed cells. Investigating distinct genotypic states in AML aims to furnish invaluable insights into the intricate web of co-mutational synergy and the influence of mutation chronology on leukemia progression, ultimately directing the development of genotype-specific therapeutic strategies and furthering the era of precision medicine in AML management.
Committee
Linde Miles, Ph.D. (Committee Chair)
Andrew Volk, Ph.D. (Committee Member)
Erin Hertlein, Ph.D. (Committee Member)
Pages
50 p.
Subject Headings
Oncology
Keywords
Acute Myeloid Leukemia
;
Co-mutational synergy
;
Clonal hematopoesis
;
Tet2
;
Npm1
;
Nras
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Refworks
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RIS
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Citations
Raval, J. (2024).
Investigating co-mutational synergy in TET2 mutant leukemic transformation.
[Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712914392187043
APA Style (7th edition)
Raval, Jahnavi.
Investigating co-mutational synergy in TET2 mutant leukemic transformation.
2024. University of Cincinnati, Master's thesis.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712914392187043.
MLA Style (8th edition)
Raval, Jahnavi. "Investigating co-mutational synergy in TET2 mutant leukemic transformation." Master's thesis, University of Cincinnati, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1712914392187043
Chicago Manual of Style (17th edition)
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Document number:
ucin1712914392187043
Download Count:
51
Copyright Info
© 2024, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.