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

Abstract

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 H3 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 stabilization 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 multilevel 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.

Engineered model of t(7;12)(q36;p13) AML recapitulates patient-specific features and gene expression profiles

“…We further confirmed the depletion of erythroid identity by subjecting both K562-t(7;12) and K562 control to induced erythroid differentiation assay by adding DMSO to the culture medium and assessing the expression of erythroid marker genes (22) ( Figure 2C; Supplementary Figure 3 ). At the beginning of the assay at erythroid day 0 (E0), we observed a lower expression of HBB and TAL1 in K562-t(7;12) compared to K562 control ( Supplementary Figure 3A ), indicating an attenuation of erythroid signatures, compatible with the myeloid bias of K562-t(7;12) colony formation.…”

Engineered model of t(7;12)(q36;p13) AML recapitulates patient-specific features and gene expression profiles

“…We further confirmed the depletion of erythroid identity by subjecting both K562-t(7;12) and K562 control to induced erythroid differentiation assay by adding DMSO to the culture medium and assessing the expression of erythroid marker genes [ 24 ] (Fig. 2C and Supplementary Fig.…”

Transcriptional variability accelerates preleukemia by cell diversification and perturbation of protein synthesis

“…Further to or concomitantly with cellular diversification and putative differential susceptibility to secondary genetic hits, the molecular programs affected by Kat2a loss can also contribute to the leukemogenic process. Ribosome biosynthetic and translation factor genes are pervasive targets of KAT2A ( 12 , 33 ), and our data suggest that destabilization of translation acts to facilitate transformation at least transiently and down-regulation of translation-associated genes may accompany preleukemia to leukemia progression. Enhanced transformation may be achieved by surveying and selection of biosynthetically quiescent cell states, which evade further diversification and respond to additional mutations with disease propagation and progression.…”

“…Kat2a NULL animals are not at a risk of myeloproliferation ( 12 ), and no recurrent KAT2A mutations have been described to date in association with hematological or solid cancers. In contrast, Kat2a ablation consistently changes cellular composition ( 12 – 14 , 33 ), making it a more likely facilitator event to generate “second hit”–responsive preleukemia cells. Future studies combining genetic barcoding and phenotyping on a time course of transformation should provide definitive evidence of such an effect.…”