In summary, we found that the loss of p300 or its chemical inhibition induced (a) a profound reprogramming of the epigenome and transcriptome of premalignant HSPCs, leading to impaired differentiation and signal transduction; (b) a unique gene expression signature in Tet2-null HSPCs, related to enhanced proliferation and oncogenicity; (c) an increase in Myb expression, which directly amplifies malignant transformation of MDS HSPCs; (d) an accelerated disease progression in multiple MDS models. This evidence concerns the gene MYB and myelodysplastic syndrome.