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

Liliana Arede, Elena Foerner, Selinde Sterre Wind, Rashmi Kulkarni, Ana Filipa Domingues, George Giotopoulos, Svenja Kleinwächter, Maximilian Mollenhauer-Starkl, Holly Davison, Aditya Chandru, Ryan Asby, Ralph Samarista, Shikha Gupta, Dorian Forte, Antonio Curti, Elisabeth Scheer, Brian James Patrick Huntly, Laszlo Tora, Cristina Pina

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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.

Original languageEnglish
Pages (from-to)165-180
JournalBlood Advances
Issue number1
Early online date15 Oct 2021
Publication statusPublished - 07 Jan 2022
Externally publishedYes

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Copyright © 2021 American Society of Hematology.


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