Project description:E1A binding protein (p300) and CREB binding protein (CBP) are two homologous histone acetyl transferases that co-activate key oncogenes such as MYC and IRF4, which are relevant transcription factors in a number of haematological malignancies. In this work, we studied the effects of CCS1477 (also known as Inobrodib), a first in class orally available inhibitor of the p300/CBP bromodomains. We found that this compound causes cell cycle arrest in a panel of different hematologic cell lines and primary samples, together with a concomitant induction of myeloid differentiation in most of the AML samples. Mechanistically, we discovered that 6 hours exposure to CCS1477 triggers a rapid and selective loss of EP300 from MYB-bound enhancers in THP1 AML cells. Interestingly, after 48 hours treatment EP300 redistributes to alternate sites to induce up regulation of differentiation genes. Displacement of EP300 from MYB-bound enhancers is significantly associated with the rapid collapse in the expression of nearby genes, most of which correspond to key myeloid identity transcription factors such as MYC, MYB, CEBPA, GFI1, SPI1 and IRF8. In most of these down-regulated genes after CCS1477 treatment, the RNA-Pol II is stalled along the gene body thus failing in completing the transcriptional elongation. In OPM2 myeloma cells, CCS1477 releases EP300 from FGFR3, the target of the common (4;14) translocation, with loss of EP300 from enhancer sites bound by IRF4. We also showed that in leukaemia patients this drug causes a substantial increase in blood neutrophil count and up-regulation of MYB-regulated differentiation genes in the population of blast cells, while in myeloma patients it conferred a sustained reduction in urinary free light chains. Overall, our study describes the molecular activity of a novel epigenetic drug in different haematological malignancy settings, with promising effects in vivo both as single agent and in combination with standard of care agents such as azacitidine and venetoclax.

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Estimating the risk of developing secondary hematologic malignancies in patients with T1/T2 prostate cancer undergoing diverse treatment modalities: A large population-based study.

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