Myelodysplastic syndromes (MDS) are hematopoietic stem and progenitor cell (HSPC) malignancies characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Epigenetic regulators are recurrently mutated in MDS, directly implicating epigenetic dysregulation in MDS pathogenesis. Here, we identified a tumor suppressor role of the acetyltransferase p300 in clinically relevant MDS models driven by mutations in the epigenetic regulators TET2, ASXL1, and SRSF2. The loss of p300 enhanced the proliferation and self-renewal capacity of Tet2-deficient HSPCs, resulting in an increased HSPC pool and leukemogenicity in primary and transplantation mouse models. Mechanistically, the loss of p300 in Tet2-deficient HSPCs altered enhancer accessibility and the expression of genes associated with differentiation, proliferation, and leukemia development. Particularly, p300 loss led to an increased expression of Myb, and the depletion of Myb attenuated the proliferation of HSPCs and improved the survival of leukemia-bearing mice. Additionally, we show that chemical inhibition of p300 acetyltransferase activity phenocopied Ep300 deletion in Tet2-deficient HSPCs, whereas activation of p300 activity with a small molecule impaired the self-renewal and leukemogenicity of Tet2-deficient cells. This suggests a potential therapeutic application of p300 activators in the treatment of MDS with TET2 inactivating mutations.
Na Man, Gloria Mas, Daniel L. Karl, Jun Sun, Fan Liu, Qin Yang, Miguel Torres-Martin, Hidehiro Itonaga, Concepcion Martinez, Shi Chen, Ye Xu, Stephanie Duffort, Pierre-Jacques Hamard, Chuan Chen, Beth E. Zucconi, Luisa Cimmino, Feng-Chun Yang, Mingjiang Xu, Philip A. Cole, Maria E. Figueroa, Stephen D. Nimer
Submitter: Thomas Gonda | thomas.gonda@unisa.edu.au
Authors: Thomas Gonda
University of South Australia and University of Queensland
Published November 5, 2021
I was very interested to read this paper as it contains some interesting and novel findings regarding p300, MYB, and myeloid neoplasia. I was quite surprised however that there was no mention in the paper at all of findings from my previous laboratory (Pattabiraman et al Blood, 123:2682-2690, 2014) that showed an absolute requirement for the interaction of MYB and p300/CBP for AML induction. Those findings have been supported by work from other groups using small molecule inhibitors (reviewed in Uttarkar et al Exp Hematol 47:31-35, 2017), or that from Kentsis laboratory (Takao et al, eLife 10:e65905, 2021) who used a synthetic peptide to block the interaction of MYB with the CBP/p300 KIX domain. There may well be ways to explain the apparent discrepancy between the essential role of this interaction from these studies, and the tumour-suppressor-like role reported for p300 by Man and colleagues. For example, redundancy between p300 and CBP may allow MYB to exert its oncogenic effects in the absence of p300. In any case, I would have thought this would have warranted some discussion at least.
Submitter: Stephen D. Nimer | nimer@med.miami.edu
Authors: Na Man, Gloria Mas Martin, and Stephen D. Nimer
Published November 5, 2021
We very much appreciate Dr. T. Gonda’s comments on our work. We wish to address the overall mechanism behind the effects that we reported, and by so doing address the work we have cited.
As Gonda points out, there are numerous reports implicating Myb expression in leukemogenesis. Their work and that of others have shown that a p300-Myb interaction can drive leukemogenesis and that small molecule blockers, or mutations in p300 and Myb that abrogate the p300-Myb interaction can be effective inhibitors of leukemia initiation and cell growth. Gonda’s 2014 Blood paper showed the importance of the p300- Myb interaction for both AML1-ETO (AE) and MLL-AF9 driven AML. They show that the interaction is required for AE to block differentiation, and to generate AML in mouse fetal liver or bone marrow cells. We wish to point out that in these cases, p300 is functioning to promote leukemia.
We have also reported that p300 can promote leukemia and that p300 inhibitors have anti-AML effects. We first observed this for AE driven AMLs (Wang et al Science 2011), where we showed the importance of lysine 43 (K43) acetylation in AE driven AML, and that p300 inhibitors can impair the growth of AE positive and negative AML cell lines. However, in the Man et al paper we show that the absence of p300 can trigger leukemia in four distinct MDS mouse models. Although Myb expression increases, in the absence of p300 or by using the p300/CBP inhibitor A-485, Myb target genes become downregulated. We speculate that, in the absence of p300 or its catalytic activity, Myb is unable to act as a co-activator and instead acts as a repressor of transcription. This hypothesis remains to be worked out, hopefully by us and others.
Regarding any oversight in not citing the Pattabiraman et al Blood, 2014 from the Godna laboratory; first, we did cite one publication by Gonda et al (reference 35) and also one publication by Uttarkar (reference 42). Thus, we did and certainly do acknowledge the series of studies by Gonda and colleagues in contributing to our knowledge of Myb activity in hematopoiesis and malignancy. Second, we did not cite the study by Kentsis at least in part due to an active collaboration with their lab on extending the work we have published. We continue to explore how Myb functions in the absence of p300 in driving leukemogenesis.