GSE114962
RNA-seq profiling of a mouse B cell lymphoma cell line treated with the KAT6A/B inhibitor WM-1119
Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function. The MYST family of KATs (KAT5-8) includes the oncogenes KAT6A (MOZ) and KAT6B (MORF/QKF). KAT6A has essential roles in normal hematopoietic stem cells and is the target of recurrent chromosomal translocations, causing acute myeloid leukemia. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers. KAT6A suppresses cellular senescence via regulation of suppressors of the CDKN2A locus, a function that requires its KAT activity. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. We have produced a series of highly potent, selective inhibitors of KAT6A/B including WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible acetyl-CoA competitors and inhibit MYST-catalyzed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF dependent and accompanied by gene expression changes typical of loss of KAT6A function. We anticipate that this class of inhibitors will be useful in accelerating development of therapeutics targeting gene transcription regulated by histone acetylation. We show that WM-1119 arrests lymphoma progression in mice. The B cell lymphoma cell line, EMRK1184, was isolated from Eµ-Myc transgenic mice, which are mice with a tumor resulting from the expression of cMyc under the control of the IgH enhancer. EMRK1184 expresses the Cdnk2a locus-encoded ARF and wild type p53. Treatment with WM-1119 inhibited the proliferation of the EMRK1184 lymphoma cells in vitro. RNA-seq and Western blot analysis showed that WM-1119 treatment resulted in increased levels of Cdkn2a and Cdkn2b mRNA and P16INK4a and p19ARF protein, as well as a delayed increase in Cdkn1a mRNA. The data here present RNA-seq profiling of EMRK1184 lymphomas treated with either WM-1119 or a control. Overall design: EMRK1184 cells were infected with a luciferase-expressing lentiviral imaging construct to allow quantitation of tumor burden throughout treatment, producing the EMRK1184luc cell line. EMRK1184luc cells were treated with WM-1119 or a control and profiled by RNA-seq. Three biological replicates per treatment condition were prepared and sequenced. RNA-seq was undertaken for n=3 samples treated with DMSO for 3 days, n=3 samples treated with DMSO for 6 days, n=3 samples treated with WM-1119 for 3 days and n=3 samples treated with WM-1119 for 6 days.