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Title: The cell-essentiality of KAT7 in acute myeloid leukemia
Author: Au, Yan Zi
ISNI:       0000 0004 8500 3787
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy, characterized by the uncontrolled proliferation and differentiation arrest of myeloid progenitors. Chemotherapy has been the front-line treatment for decades and cure remains elusive for the majority of AML patients. Genome-wide CRISPR-Cas9 screens have previously identified KAT7 as an AML-specific cell-essential gene and therefore may represent a potential novel therapeutic target for AML. Here, I show that KAT7 loss leads to a rapid and dramatic global reduction in both H3K14ac and H4K12ac in association with reduced proliferation, increased apoptosis or enhanced differentiation of AML cells driven by the translocation of Mixed-lineage leukemia (MLL) gene. Mice transplantation with KAT7 knock-out AML cell line showed delayed disease progression and prolonged survival compared to those injected with the wild-type counterpart. The acetyltransferase activity of KAT7 is essential for MLL-fusion AML as the E508Q catalytic dead mutant is unable to sustain the leukemic programme. Using the auxin-inducible degron (AID) system to induce rapid KAT7 protein degradation, I showed that KAT7 is required for the recruitment of the MLL-fusion associated adaptor proteins such as BRD4 and AF4 to gene promoters, which are critical for the maintenance of the MLL-AF9 transcriptional programme. Although not found to be mutated among cases of AML, KAT7 is a plausible therapeutic target for this poor prognosis subtype of AML.
Supervisor: Vassiliou, George Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Acute myeloid leukemia ; mll-fusion ; KAT7 ; MYST