Molecular Mechanisms and Therapies for Radiation-Induced Myelodysplastic Syndrome (MDS) - Liang (formerly van Zant) Scope

Myelodysplastic Syndrome (MDS) refers to a collection of hematologic diseases with several common characteristics, the most fundamental of which is progressive bone marrow failure. Patients, usually 60-75 years old, often present with refractory anemia and this was the basis of nomenclature used for clinical staging. Roughly one third of patients diagnosed with MDS go on to develop acute myelogenous leukemia (AML). Prognosis for the severity and tempo of MDS progression is correlated with a collection of several karyotypic changes. Perhaps the most defining of which is deletions on the short arm of chromosome 5, leading to the name 5Q Syndrome. MDS is a bone marrow stem cell disease leading to inadequate production of red and white cells of the myeloid lineages. As with most malignancies, progressive genetic changes in stem cells due to aging, environmental insult, chemotherapy, and radiation treatment, culminate in sufficient damage to significantly degrade the functional capacity of the stem cell population. Therefore, MDS is frequently an unfortunate long-term consequence of radiation treatment of solid tumors; for example, of the breast and prostate. The overarching aim of this project is to better understand how radiation causes damage to the stem cell population that leads to MDS, how the damage may be averted or repaired, and how practical results of this knowledge can be applied clinically. A multi-center project is formed that draws on the strengths of researchers at the University of Kentucky (UK), Cincinnati Children’s Hospital Medical Center (CCHMC), and the University of Arkansas (UA). As the Principal Investigator of one of subprojects, my lab is focused on investigation of two aspects of MDS: 1) MDS mouse model, and 2) age-related genome-wide epigenetic changes of bone marrow stem cells. Specifically, I am interested in a novel stem cell regulatory gene, latexin, and its in vivo function in MDS development by using mouse genetic models as well as patients’ samples. Our preliminary study suggests that loss of latexin function promotes radiation and replicative stress-induced myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). Therefore, latexin knockout mouse model provides a platform to study tumorigenesis of t-MDS/AML and to be used as a pre-clinical tool for examining drug efficacy. More importantly, I identified a single nucleotide polymorphism (SNP) that affects the natural expression variation of latexin expression in bone marrow stem cells. Thus, I hypothesize that latexin expression level and/or SNP in its promoter could be as a biomarker to predict the risk for t-MDS/AML in cancer patients receiving radio- and chemo-therapy. We are currently investigating: 1) The role of latexin gene in t-MDS/AML; 2) latexin-Rps3 signaling pathways in t-MDS/AML; and 3) translational potential of latexin by studying t-MDS/AML patients-derived stem cells. Another important project in my lab is studying genome-wide epigenetic and transcriptional signatures of stem cell aging, and their relationship with age-associated increase in MDS/leukemia and decrease in tissue regeneration by using mouse genetic models and high-throughput sequencing.