Loss of p300 accelerates MDS-associated leukemogenesis

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.