Unknown

Dataset Information

0

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


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.

SUBMITTER: Domingues AF 

PROVIDER: S-EPMC7039681 | BioStudies | 2020-01-01

REPOSITORIES: biostudies

Similar Datasets

2020-02-03 | GSE118576 | GEO
2019-01-01 | S-EPMC6426930 | BioStudies
2020-02-03 | GSE118768 | GEO
2017-01-01 | S-EPMC5841452 | BioStudies
2018-01-01 | S-EPMC6334525 | BioStudies
1000-01-01 | S-EPMC5081405 | BioStudies
2019-01-01 | S-EPMC6363099 | BioStudies
2014-07-16 | E-GEOD-53427 | BioStudies
2020-01-01 | S-EPMC7206084 | BioStudies
2014-01-01 | S-EPMC3936793 | BioStudies