Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells
Ana Filipa Domingues, Rashmi Kulkarni, George Giotopoulos, Shikha Gupta, Laura Vinnenberg, Liliana Arede, Elena Foerner, Mitra Khalili, Rita Romano Adao, Ayona Johns, Shengjiang Tan, Keti Zeka, Brian J.P. Huntly, Sudhakaran Prabakaran, Cristina Pina
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.