Protein Suppresses Transformation of Myelodysplastic Syndrome to Acute Myeloid Leukemia
New research helped better explain who changes in DNA methylation and histone modification may affect development of MDS.
Deletion of p300, but not CREB-binding protein (CBP), accelerated leukemogenesis in a mouse model of myelodysplastic syndrome (MDS). In addition, p300 seems to play a pivotal role in inhibiting the transformation of MDS to acute myeloid leukemia (AML).1
Both p300 and CBP are involved in DNA methylation and histone modifications. Although they are distinct proteins, their enzymatic activity as lysine acetyltransferases acting in DNA methylation and histone modification are quite similar.
This research helped better elucidate the potential role of changes in DNA methylation and histone modification in the development of MDS and in the transformation of MDS into AML. Both p300 and CBP are mutated in several cancers, indicating potential roles as tumor suppressors.
In this study, researchers separately deleted p300 and CBP in Nup98-HoxD13 transgenic mice, which are a mouse model of MDS. Deletion of p300 increased the rate of leukemogenesis in these mice, whereas deletion of CBP had no effect on the rate of leukemogenesis.
Deletion of p300 allowed hematopoietic stem and progenitor cells to regain the ability to self-renew in vitro, which was accompanied by decreased apoptosis and increased stem cell symmetric self-renewal.
Loss of p300 also promoted cytokine signaling, activating pathways involved in leukemogenesis. This type of activation did not occur with the deletion of CBP.
These results suggest a role for p300 as a tumor suppressor that inhibits the transformation of MDS into AML when p300 is functioning normally.
"The loss of p300 allows these defective cells to grow and become leukemic," explained senior author Stephen Nimer, MD, director of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Florida, in a news release on the study.2
"This work offers us a window into AML, which we are now going to try to exploit."
1. Cheng G, Liu F, Asai T, et al. Loss of p300 accelerates MDS-associated leukemogenesis [published online January 6, 2017]. Leukemia. doi: 10.1038/leu.2016.347
2. Researchers show p300 protein may suppress leukemia in MDS patients [news release]. Miami, FL: University of Miami Miller School of Medicine; March 27, 2017. http://med.miami.edu/news/Researchers-show-p300-protein-may-suppress-leukemia-in-MDS-patients-. Accessed April 11, 2017.