{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/300486"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/300486","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"The Cell-Essentiality of KAT7 in Acute Myeloid Leukemia","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Au, Yan Zi"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Vassiliou, George"],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-01-01","date_published":"2020-01-01","updated_at":"2026-07-22T22:24:28Z","subjects":["Acute myeloid leukemia","mll-fusion","KAT7","MYST"],"languages":["en"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/b65bc7f7-d16b-4149-90f8-e7ceb03c3614/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.47558","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Vassiliou, George"]},{"key":"dc:creator","label":"Author","values":["Au, Yan Zi"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2020-01-01"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/300486"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Acute myeloid leukemia","mll-fusion","KAT7","MYST"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/b65bc7f7-d16b-4149-90f8-e7ceb03c3614/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.47558"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/91da4e28-5021-4e34-bf74-34f7f1ea61dd/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy, characterized by the uncontrolled proliferation and differentiation arrest of myeloid progenitors. 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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. 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