Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells.
Ana Filipa DominguesRashmi KulkarniGeorge GiotopoulosShikha GuptaLaura VinnenbergLiliana AredeElena FoernerMitra KhaliliRita Romano AdaoAyona JohnsShengjiang TanKeti ZekaBrian J HuntlySudhakaran PrabakaranCristina PinaPublished in: eLife (2020)
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.
Keyphrases
- acute myeloid leukemia
- transcription factor
- single cell
- cell fate
- rna seq
- gene expression
- allogeneic hematopoietic stem cell transplantation
- dna binding
- genome wide
- dna methylation
- genome wide identification
- high throughput
- copy number
- public health
- dna damage
- stem cells
- high frequency
- heat shock
- young adults
- acute lymphoblastic leukemia
- cell therapy
- heat shock protein
- childhood cancer