Member Biography

One major current and future research focus of mine is on the role of DEK in regulating normal hematopoiesis, acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). DEK is a unique DNA-binding protein that plays a role in gene regulation through its ability to stabilize heterochromatin. Most interestingly it can be secreted extracellularly by immune cells upon stimulation by IL-8 and other inflammatory mediators and work as a ‘danger signal’ stimulating an immune response. Current work from our laboratory suggests that extracellular DEK can regulate normal hematopoiesis as well in two different ways. First, extracellular DEK can inhibit hematopoietic progenitor cell (HPC) numbers and cycling and increase hematopoietic stem cell (HSC) numbers in a CXCR2-dependent manner. Interestingly DEK, upon examination of its amino acid sequence, was discovered to contain an ELR-motif similar to that of the chemokine IL-8 which binds to CXCR2. Second, extracellular DEK can bind to heparan sulfate-type proteoglycans (HSPGs) on the surface of HSC/HPCs, become internalized, and stabilize heterochromatin which can lead to a reduction in cellular proliferation/differentiation. This process can be blocked by neutralizing the HSPGs thus inhibiting the DEK-mediated reduction in HPC numbers. Although extracellular DEK regulates normal hematopoiesis, there is little to no understanding as to whether or not DEK can regulate leukemia cancer initiating cells (CICs) or influence the pathogenesis of MDS and/or AML. AML and MDS are heterogeneous malignancies associated with multiple morphologic, cytogenetic and molecular abnormalities. Despite the use of multiple novel therapeutics, there is still a high incidence of relapse and poor clinical outcome for patients with these diseases. Failure to receive durable remission in these patients is often due to the fact that the therapies utilized do not directly target the cancer-initiating cell (CIC) populations. Recently it was discovered that MDS and AML CICs, which can be found in multiple different HSC and HPC lineages, greatly overexpress IL-8 and CXCR2. This signaling pathway provides a pro-growth/survival signal to CICs. The patients with MDS or AML that overexpresses CXCR2 have a poor clinical outcome indicating that the IL-8:CXCR2 pathway may be a key novel therapeutic target in these patients. The fact that DEK secretion is mediated by IL-8, that DEK needs to bind to CXCR2 to inhibit HPC numbers, and that DEK can be internalized and regulate heterochromatin stability, led us to hypothesize that extracellular DEK may play an important role in regulating MDS/AML disease pathogenesis and progression by disrupting the IL-8:CXCR2 axis. This work has received funding from a Pilot Project Grant from the American Cancer Society Institutional Research Grant #IRG-16-192-31 through the Melvin and Bren Simon Cancer Center and is currently on going. Another major project currently underway is examining the effects of isolating and processing bone marrow under hypoxic conditions, especially that of aged mice. Bone marrow (BM) of aged mice have increased HSCs, but greatly decreased competitive engrafting capability with decreased lymphoid capability compared to young mice. HSCs and HPCs reside in vivo in a hypoxic (e.g. ~3% O2) environment compared to ambient air (~21% O2). Yet, until recently knowledge of HSCs and HPCs was based on cells collected in ambient air, thus underestimating numbers of HSCs. Within minutes of exposure to ambient air, mitochondrial-derived ROS levels are increased, inducing rapid differentiation, not death, of HSCs. We hypothesized that that functional status of BM HSCs and HPCs from aged mice does not reflect their true nature. Thus we re-evaluated BM of 6-10 week and 20-28 month old C57Bl/6 mice collected at 3% compared to 21% O2. BM collected from old mice under hypoxia had increased engrafting capability more closely matching that of young BM. The lymphoid/myeloid ratio of old BM collected under hypoxia matched that of young BM collected under air. Enhanced numbers/function of old BM HSCs/HPCs collected in hypoxia is associated with changes in expression of CXCR4, CCR5, and ROS. Thus, the age related differences between the HSC/HPC populations are not as drastic as previously reported.

Post-doctoral Fellowship - Indiana University School of Medicine, Indianapolis, IN 2016

Ph.D. - State University of New York at Buffalo-Buffalo, NY 2012