Jing Fang, MD, PhD | Aplastic Anemia and MDS International Foundation

Jing Fang, MD, PhD

Mechanisms linking p62/SQSTM1 to the Evolution of Myelodysplastic Syndrome
Original Research Center: 
Cincinnati Children’s Hospital Medical Center, Cancer and Blood Disease Institute
Pubmed Author Name: 
Fang J

A major complication of myelodysplastic syndromes (MDS) is worsening cytopenias due to bone marrow failure. Novel therapeutic approaches are urgently needed for MDS, as current therapies have modest responses and many patients are not suitable candidates for bone marrow transplantation. Our preliminary study revealed a role of sequestosome 1/p62 in the pathogenesis and disease evolution of MDS. For this study, we will dissect the functional domains on p62 and associated signaling pathways that are necessary for the development and maintenance of MDS. Moreover, we propose to target p62-intacting complexes using a peptide approach as an attempt to target MDS clones and prevent disease evolution. This study will improve our understanding of MDS-associated bone marrow failure and may reveal new therapeutic strategies.

First Year Report: 

Myelodysplastic syndromes (MDS) are a group of aggressive blood diseases that results in low blood cell production and a risk of developing leukemia. A major obstacle in treating MDS is that the mechanism of the development of MDS is underexplored and few mouse models faithfully recapitulating the clinical features of MDS are available. We recently identified a multifunctional protein p62 whose expression level is increased in blood-forming cells of MDS patients. With a genetic approach, we generated a novel mouse model in order to understand whether and how increased p62 drives MDS. Within this model, we genetically increased p62 expression specifically in blood-forming cells in the mouse. The p62-expressing mouse model will help us understand the consequence of increased p62 in blood-forming cells and mature blood cells. p62 has been shown to interact with specific proteins and regulate critical cellular function. We will identify p62-interacting proteins and associated signaling pathways that are required for the development of MDS in p62-exressing mice. We will also design and examine therapeutic peptides that specifically disrupt the interaction between p62 and the associated proteins as a means to inhibit MDS cells and recover normal blood formation.