Grants and Grant Recipients

Aplastic Anemia is a disease that results in the destruction of hematopoietic stem cells in the bone marrow by the immune system. Although the exact mechanism of this pathology is not fully understood, the prevailing model proposes that the immune system and specifically T cells are responsible for this destruction. Pediatric and adult aplastic anemia, while clinically similar in their presentation may in fact be representative of different subsets of a spectrum of aplastic anemia. Our group and others have shown that adult patients with aplastic anemia have a tendency to develop cell populations that are predisposed to myelodysplastic syndrome and leukemia. In the pediatric population however, we found that patients tend to develop cell populations that have mutations in certain genes (i...

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by inefficient blood production. MDS represents the most common cause of acquired bone marrow failure in adults and there are few effective therapies for the majority of MDS patients. In 2011, it was discovered that mutations in proteins encoding RNA splicing factors (SFs) are the most common class of mutations in patients with MDS and chronic myelomonocytic leukemia (CMML). Despite these discoveries, however, we do not yet fully understand why abnormal RNA splicing results in MDS nor do we have therapies that specifically target MDS cells bearing this common class of mutations. The goals of this proposal are two-fold: (1) to determine the efficacy of clinical-grade novel spliceosome inhibitors in...

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...