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bioRxiv · 10.1101/446096

Loss Of Kat2a Enhances Transcriptional Noise And Depletes Acute Myeloid Leukemia Stem-Like Cells

Domingues, A. F.·Kulkarni, R.·Giotopoulos, G.·Gupta, S.·Tan, S.·Foerner, E.·Romano Adao, R.·Zeka, K.·Huntly, B. J.·Prabakaran, S.·Pina, C.
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Abstract

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective myelo-monocytic 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, we demonstrate that Kat2a contributes to leukemia propagation through homogeneity of transcriptional programs and preservation of leukemia stem-like cells. Kat2a loss reduces transcriptional bursting frequency in a subset of gene promoters, generating enhanced variability of transcript levels but minimal effects on mean gene expression. Destabilization of target programs shifts cellular equilibrium out of self-renewal towards 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 at distinct stages of cancer evolution.

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Domingues, A. F., Kulkarni, R., Giotopoulos, G., Gupta, S., Tan, S., Foerner, E., Romano Adao, R., Zeka, K., Huntly, B. J., Prabakaran, S., Pina, C.. 2018-10-18. Loss Of Kat2a Enhances Transcriptional Noise And Depletes Acute Myeloid Leukemia Stem-Like Cells. https://doi.org/10.1101/446096

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