KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia

Author notes: *E.F. and S.W. contributed equally to this study. ChIP-seq and A-seq data have been deposited in GEO (accession numbers GSE128902 and GSE128512). Send data sharing requests via e-mail to the corresponding author. The full-text version of this article contains a data supplement.Copyright © 2021 The Authors. Epigenetic histone modifiers are key regulators of cell fate decisions in normal and malignant hematopoiesis. Their enzymatic activities are of particular significance as putative therapeutic targets in leukemia. In contrast, less is known about the contextual role in which those enzymatic activities are exercised, and specifically, how different macromolecular complexes configure the same enzymatic activity with distinct molecular and cellular consequences. We focus on KAT2A, a lysine acetyltransferase responsible for Histone 3 Lysine 9 acetylation, which we recently identified as a dependence in Acute Myeloid Leukemia stem cells, and that participates in 2 distinct macromolecular complexes: Ada Two- A-Containing (ATAC) and Spt-Ada-Gcn5-Acetyltransferase (SAGA). Through analysis of human cord blood hematopoietic stem cells and progenitors, and of myeloid leukemia cells, we identify unique respective contributions of the ATAC complex to regulation of biosynthetic activity in undifferentiated self-renewing cells, and of the SAGA complex to stabilisation or correct progression of cell type-specific programs with putative preservation of cell identity. Cell type and stage-specific dependencies on ATAC and SAGA-regulated programs explain multi-level KAT2A requirements in leukemia and in erythroid lineage specification and development. Importantly, they set a paradigm against which lineage specification and identity can be explored across developmental stem cell systems.Rosetrees Trust PhD Studentship; Kendall Leukaemia Fund Intermediate Fellowship (KKL888); Leuka John Goldman Fellowship for Future Science (2017); Wellcome Trust/University of Cambridge ISSF Grant; Lady Tata Memorial Trust PhD Studentship; Trinity Henry Barlow Trust Studentship; NIH RO1 grant (1R01GM131626-01); Agence Nationale de la Recherche (ANR) Program grants (AAPG2019 PICen, PRCI AAPG2019 EpiCAST, ANR-10-LABX-0030-INRT, frame program Investissements d’Avenir ANR-10IDEX-0002-02); Brunel University

A redundant flight recovery system implementation during an octocopter failure

This research presents a redundant flight recovery system during a motor failure in an octocopter platform. This proposed recovery system exploits the property that the octocopter can be derived by combining two quadrotor systems. During motor failure, the octocopter switches to a stable quadrotor flight configuration while immediately landing the octocopter to prevent further damage to installed sensor and equipment and the octocopter platform. The redundant system utilizes PID and fuzzy logic controllers to stabilize altitude and attitude respectively. © 2016 IEEE

MAT2A inhibition in AML unveils therapeutic potential of combining DNA demethylating agents with UPR targeting

This article is a preprint and has not been certified by peer review.Data availability: RNA-seq data were deposited in EBI Biostudies under accession E-MTAB-12847 (FIDAS-5) and E-MTAB-12848 (single and combinatorial CB and AZA treatments).Acute Myeloid Leukaemia (AML) is a heterogeneous disease of dismal prognosis, with vulnerabilities in epigenetic and metabolic regulation. DNA demethylating agents, e.g. azacytidine (AZA), are used as first-line therapy in AML patients unable to tolerate intensive chemotherapy regimens, often in combination with BCL-2 inhibitor venetoclax. However, the impact on survival is limited, indicating the need for alternative therapeutic strategies. Methyl-group usage for epigenetic modifications depends on methionine availability and MAT2A-driven conversion to S-adenosyl-methionine. Methyl-group production is a vulnerability in multiple tumours, including AML, and has been variably linked to impairment of different histone methyl-modifications. In contrast, we herein align MAT2A effects in AML with DNA methylation and proteostasis. We show that MAT2A inhibition can be mimicked by combining AZA with unfolded protein response (UPR) activation through targeting of valosin-containing protein (VCP)/P97. Combined AZA and P97 inhibition exceeded AZA-driven restriction of human AML cell expansion, and specifically impaired colony-formation and maintenance of CD34+ patient blasts, suggesting targeting of AML stem/progenitor-like cells. Overall, our data support combined targeting of DNA methylation and the UPR as a promising therapeutic strategy in AML.This work was funded by a Leuka John Goldman Fellowship for Future Science (2017-2019), a Wellcome Trust/University of Cambridge ISSF grant (2019), and a British Society for Haematology Early-Stage Grant (2020-2022) to CP. KZ was funded by a MSCA Post-Doctoral Fellowship (2017-800274). D.F. was supported by Associazione Italiana Ricerca sul Cancro (AIRC-Fellowship 20930 for Abroad). EM was funded by an European Research Council Consolidator Grant (647685) awarded to BJPH. BJPH was also supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) and Wellcome Trust who funded the Wellcome – MRC Cambridge Stem Cell Institute (203151/Z/16/Z)