Understand the Biology Driving Clinical Responses for Patients with FLT3 and NPM1 Mutations Dr. Stirewalt’s lab was one of the first to examine the clinical significance of FLT3 mutations in AML. This work led to the recognition of FLT3 internal tandem duplications (ITDs) and NPM1 mutations as two of the most clinically utilized prognostic factors for AML patients, especially those with normal cytogenetics. Subsequent studies from the lab have found that the biology and clinical significance of these mutations differ depending on specific characteristics of the mutation (i.e., mutation size, its location within the gene, allelic ratio, etc.), other cooperative molecular events (e.g., DNMT3A mutations), and age of the patient. Currently, our research projects investigating FLT3 and NPM1 focus on understanding the mechanisms driving the heterogeneous molecular biology and clinical significance of these mutations in AML. These studies are utilizing innovative technologies such as next generation sequencing, proteomics, and transfection/transduction models.
Identify Novel AML Prognostic Biomarkers and Therapeutic Targets Many AML patients do not harbor either NPM1 or FLIT3 mutations; therefore, there is a need for additional prognostic biomarkers to better risk-stratify these patients. To identify novel prognostic factors and potential therapeutic targets, we are examining differences in the global genomic and expression profiles between normal hematopoietic cells and AML blasts. Our previous studies have identified 13 genes with AML-specific expression changes, some of which may be novel prognostic factors and/or potential therapeutic targets, with several showing potential as novel adoptive immune targets. We are collaborating with other investigators to provide a more global assessment of the entire molecular landscape including protein expression and phosphorylation.
Understand the Role of Aging in the Development of Hematopoietic Malignancies As with most malignancies, the incidence of hematopoietic malignancies (AML, CML, MDS) increases with age, and as such, a better understanding of the molecular biology of the aging hematopoietic system may provide insight into hematopoietic transformation. Through previous NIH-supported studies, we identified a number of genes with age-related expression changes in normal hematopoietic progenitor/stem cells and AML blasts. Moreover, we and others have found that some of these age-related genes play critical roles in normal hematopoiesis and malignant transformation. Given the results from our previous work, we are expanding our studies of aging to include a larger cohort of normal and malignant samples and to examine an even broader spectrum of expression changes (e.g., proteomics, alternative splicing, microRNA).
