| Autor: |
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 Huntly, Sudhakaran Prabakaran, Cristina Pina |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
eLife, Vol 9 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
2050-084X |
| DOI: |
10.7554/eLife.51754 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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