| First Author | Domingues AF | Year | 2020 |
| Journal | Elife | Volume | 9 |
| PubMed ID | 31985402 | Mgi Jnum | J:290681 |
| Mgi Id | MGI:6443305 | Doi | 10.7554/eLife.51754 |
| Citation | Domingues AF, et al. (2020) Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells. Elife 9:e51754 |
| abstractText | 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. |
