The Cell-Essentiality of KAT7 in Acute Myeloid Leukemia

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.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Au, Yan Zi

Advisor dc:contributor.advisor

• Vassiliou, George

• Acute myeloid leukemia
• mll-fusion
• KAT7
• MYST

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/b65bc7f7-d16b-4149-90f8-e7ceb03c3614/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.47558

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/300486