MS, University of Cincinnati, 2024, Medicine: Cancer and Cell Biology

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 developmen (open full item for complete abstract)

Committee: Linde Miles Ph.D. (Committee Chair); Andrew Volk Ph.D. (Committee Member); Erin Hertlein Ph.D. (Committee Member) Subjects: Oncology