Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells.

Ana Filipa Domingues,George Giotopoulos,Brian J Huntly,Ayona Johns,Laura Vinnenberg,Cristina Pina,Liliana Arede,Rashmi Kulkarni,Rita Romano Adao,Shikha Gupta,Mitra Khalili,Shengjiang Tan,Elena Foerner,Sudhakaran Prabakaran,Keti Zeka

doi:10.7554/elife.51754

Abstract

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective white blood cell differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity, that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics of a conditional knockout mouse, we demonstrate that Kat2a contributes to leukemia propagation through preservation of leukemia stem-like cells. Kat2a loss impacts transcription factor binding and reduces transcriptional burst frequency in a subset of gene promoters, generating enhanced variability of transcript levels. Destabilization of target programs shifts leukemia cell fate out of self-renewal into differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and distinct stages of cancer evolution.

Highlights

Acute Myeloid Leukemia (AML) is the most prevalent leukemia in adults with a dismal prognosis of less than 30% 5 year survival (Dohner et al, 2017)
In order to investigate the impact of Kat2a loss on self-renewal vs. differentiation of AML stem-like cells (AML-SC), we generated an inducible conditional Kat2aFl/Fl KO mouse model and transformed Kat2a excised (KO) and non-excised (WT) bone marrow (BM) cells through retroviral delivery of an MLL-AF9 fusion transcript
Mx1-Cre-positive (KO) and Mx1-Cre-negative (WT) mice were compared across all experiments (Figure 1—figure supplement 1A), with locus excision obtained through treatment of experimental and control mice with intra-peritoneal polyinosylic-polycytidylic acid (Chan et al, 2011)

Summary

Introduction

Acute Myeloid Leukemia (AML) is the most prevalent leukemia in adults with a dismal prognosis of less than 30% 5 year survival (Dohner et al, 2017). It is a heterogeneous disease, clinically and pathologically, with common cellular themes of myeloid differentiation block, and recurrent molecular targeting of chromatin and transcriptional regulators. Specific examples of AML dependence on unmutated chromatin regulators include BRD4 (Dawson et al, 2011; Zuber et al, 2011), LSD1 (Harris et al, 2012) or DOT1L (Bernt et al, 2011; Daigle et al, 2011), their importance highlighted by the fact that chemical

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