Micrograph showing MDS
The protein p300 may prevent the transformation from myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML), according to research published in Leukemia.
Researchers found that loss of p300 “markedly” increased leukemogenesis in a mouse model of MDS.
“The loss of p300 allows these defective [MDS] cells to grow and become leukemic,” said study author Stephen Nimer, MD, of Sylvester Comprehensive Cancer Center in Miami, Florida.
“This work offers us a window into AML, which we are now going to try to exploit.”
Previous research suggested that p300 and CBP (both histone lysine acetyltransferases) may be tumor suppressors. The current study indicates that, in the context of MDS, that is only true for p300.
The researchers evaluated the effects of deleting both p300 and CBP in Nup98-HoxD13 (NHD13) transgenic mice, a model of human MDS.
The team found that p300 deletion, but not CBP deletion, accelerated leukemogenesis in the mice.
“When we eliminated p300, 100% of the mice developed leukemia,” Dr Nimer said. “It indicated that, under this specific circumstance, p300 is a tumor suppressor, offering great insight into how MDS converts to leukemia. It was quite surprising that CBP plays no role at all.”
The researchers also found that deleting p300 restored the ability of NHD13-expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew, and p300 deletion decreased apoptosis.
“While investigating how p300 functions in MDS cells, we found that MDS cells do not grow well in the lab,” Dr Nimer said. “However, when you eliminate p300, suddenly, the cells continue to grow.”
On the other hand, deletion of p300 did not have a significant effect on wild-type hematopoiesis.
Finally, the researchers found that p300 deletion enhanced cytokine signaling in NHD13-expressing HSPCs. They observed enhanced activation of the MAPK and JAK/STAT pathways in HSPCs isolated from NHD13 transgenic mice.
The team said more research is needed to understand exactly how p300 controls MDS cells, but these findings could ultimately help MDS patients avoid AML.
“Other than chemotherapy, right now, there’s no way to prevent MDS from developing into myeloid leukemia,” Dr Nimer said. “However, drugs are being developed that can promote p300 function and possibly prevent MDS patients from developing leukemia.”
