Zeng and Madlambayan team up to study leukemia

CBR members Xiangqun Zeng (Department of Chemistry) and Gerard Madlambayan (Department of Biological Sciences) have teamed up to study endothelial cell activation and their subsequent binding with leukemic cell lines. Their results are presented in a paper in the June 15, 2014 issue of Biosensors and Bioelectronics (Volume 56, Pages 151-158). The lead author is Liang Tan, a former post doc working in Zeng’s lab. Coauthors include Peiling Lin, a former graduate student working with Zeng, Bahareh Pezeshkian, a graduate student working with Madlambayan, and Abdul Rehman, a Visiting Professor in the Department of Chemistry. Excerpts from the introduction to their paper (with references removed) is given below.

Endothelial cell (EC) activation and its subsequent intercellular interactions can have significant effects on the regulation of various inflammatory responses and can be causative in generating altered microenvironments that play a role in many biological disorders, such as leukemia and drug induced vascular injuries. It has been shown that various factors (e.g. TNF-α, leukemic cells) can induce EC activation resulting in altered cell morphology as well as increased expression of various cytokines and cell adhesion molecules (CAMs) such as E-selectin, ICAM and VCAM ... Many of these molecules serve as biomarkers for EC activation, with the kinetics of expression directly correlating to the extent of EC activation. Furthermore, these molecules also support leukemic blast and leukemia initiating stem cell (LSC) adhesion to ECs, thereby making a significant contribution in leukemic growth and survival. We recently demonstrated the direct role of EC activation in promoting chemoresistance of acute myeloid leukemia (AML) cells. We found that AML cells were able to induce the activation of resting ECs leading to subsequent adhesion of AML cells through CAMs including E-selectin. Adherence induced a quiescent phenotype that protected AML cells from chemotherapy. Interestingly, adherent leukemia cells could later detach and become proliferative, initiating a process resembling relapse. Furthermore, differing leukemia subtypes modulate the EC activation process to varying degrees, which may explain the varied chemotherapeutic responses and relapse rates in different patients. These studies suggest that methods to analyze the propensity of patient specific AML cells to activate ECs may provide an indication of response to therapy and prospectively measure the likeliness of relapse.

…We believe that EC activation and subsequent leukemia cell adherence can serve as a novel model, and first ever example, to test our strategy. A cross-validation of the [quartz crystal microbalance] results with electrochemical measurements and microscopic observations, in conjunction with our detailed biological study of these events shows a strong coherence of the results. Moreover, the technological and procedural ease of this presented protocol is quite significant. Thus, a simple but efficient strategy is presented here which not only provides important information regarding EC activation and subsequent adherence of leukemia cells in real-time, but also can be employed for discrimination and quantification of two kinds of leukemia cells. Thereby, this biosensor construct aims to identify disease stage and potential for relapse as well as aiding in identifying best course of chemotherapy treatment for patients with leukemia in the near future.

This research was supported by a grant to Zeng from the National Institutes of Health (R21EB009513)