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Loss of p300 accelerates MDS-associated leukemogenesis
1Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL,USA.
Abstract:
The role that changes in DNA methylation and histone modifications have in human malignancies is poorly understood. p300 and CREB-binding protein (CBP), two distinct but highly homologous lysine acetyltransferases, are mutated in several cancers, suggesting their role as tumor suppressors. In the current study, we found that deletion of p300, but not CBP, markedly accelerated the leukemogenesis ofNup98-HoxD13 (NHD13) transgenic mice, an animal model that phenotypically copies human myelodysplastic syndrome (MDS). p300 deletion restored the ability of NHD13 expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew in vitro, and to expand in vivo, with an increase in stem cell symmetric self-renewal divisions and a decrease in apoptosis. Furthermore, loss of p300, but not CBP, promoted cytokine signaling, including enhanced activation of the MAPK and JAK/STAT pathways in the HSPC compartment. Altogether, our data indicate that p300 has a pivotal role in blocking the transformation of MDS to acute myeloid leukemia, a role distinct from that of CBP.
Insights
Deletion of p300, a protein lysine acetyltransferase, accelerates myeloid leukemia in mice, unlike CBP. Loss of p300 enhances hematopoietic stem cell self-renewal and promotes leukemogenesis, distinct from CBP's role.
Area of Science:
- Epigenetics and Cancer Biology
- Hematopoiesis
- Molecular Oncology
Background:
- The roles of DNA methylation and histone modifications in human cancers are not fully understood.
- p300 and CREB-binding protein (CBP) are homologous lysine acetyltransferases implicated as tumor suppressors due to mutations in various cancers.
Purpose of the Study:
- To investigate the distinct roles of p300 and CBP in leukemogenesis using a mouse model.
- To determine the impact of p300 deletion on hematopoietic stem and progenitor cell (HSPC) function and signaling pathways.
Main Methods:
- Utilized Nup98-HoxD13 (NHD13) transgenic mice, an established model for myelodysplastic syndrome (MDS).
- Assessed the effects of p300 deletion on leukemogenesis, HSPC self-renewal, apoptosis, and in vivo expansion.
- Analyzed cytokine signaling pathways, including MAPK and JAK/STAT, in HSPCs following p300 loss.
Main Results:
- Deletion of p300, but not CBP, significantly accelerated leukemogenesis in NHD13 transgenic mice.
- p300 deletion enhanced HSPC self-renewal and in vivo expansion by increasing symmetric self-renewal divisions and reducing apoptosis.
- Loss of p300 promoted cytokine signaling and activated MAPK and JAK/STAT pathways in HSPCs.
Conclusions:
- p300 plays a critical role in preventing the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia.
- The tumor-suppressive function of p300 in this context is distinct from that of CBP.
- p300 acts as a key regulator of HSPC homeostasis and signaling, crucial for blocking myeloid leukemia development.
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