The Role of Jarid2 in Leukemic Transformation of Myelodysplastic Syndromes
EvansMDS Young Investigator Award
Hematopoietic stem cells (HSCs) in the bone marrow are responsible for the lifelong regeneration of the blood and bone marrow. During the lifetime of an individual, genetic mutations can occur in HSCs that slightly alter their properties, potentially leading to diseases of excessive or deficient production of blood cells. When myeloid cells are chronically affected, these conditions fall into two main categories called myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). These disorders are the most common blood cancers in adults with ~20,000 new cases diagnosed each year in the United States. While these diseases lead to clinically relevant problems such as excessive bleeding and increased susceptibility to infections, in a significant number of patients the disease transforms to a leukemia that is much more difficult to treat and rapidly proves fatal (typically about five months). It is important to identify the genetic processes associated with leukemic progression of MDS and MPN to improve treatment of these patients. We have identified a new pathway that facilitates this process by identifying genetic mutations in JARID2 which occur specifically in the leukemia phase of the disease, but not the preceding MDS phase. The goal of this work is to understand the molecular programs that are dysregulated in the context of mutant JARID2, which facilitate MDS to sAML transformation. Identification of such downstream pathways may serve as therapeutic targets for JARID2-deleted leukemia. As there are no effective therapies for these patients that progress to leukemia, any findings that improve the diagnosis and treatment of these patients would represent a significant advance in this field.
Hamza Celik, Won Kyun Koh, Ashley C. Kramer, Elizabeth L. Ostrander, Cates Mallaney, Daniel A.C. Fisher, Jingyu Xiang, William C. Wilson,1 Andrew Martens, Alok Kothari, Gregory Fishberger, Eric Tycksen, Darja Karpova, Eric J. Duncavage, Youngsook Lee, Stephen T. Oh, and Grant A. Challen, JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells, Cancer Cell 2018, doi: 10.1016/j.ccell.2018.10.008