Cell Mechanics of Leukostasis in Acute Leukemia
- Author(s): Lam, Wilbur Aaron
- Advisor(s): Fletcher, Daniel
- et al.
Leukostasis, a complication of acute leukemia, occurs when leukemia cells aggregate in and obstruct the microvasculature, leading to profound damage of vital organs like the brain and lungs. The underlying mechanisms are poorly understood but are likely related to the abnormal mechanical properties of leukemia cells. Little improvement has been made in our understanding of leukostasis in the last several decades due in part to a lack of tools to sensitively measure leukemia cell biophysical properties, such as cell stiffness and adhesiveness. Accordingly, no reliable methods currently exist to predict, treat or prevent leukostasis.
Using an atomic force microscopy (AFM) technique I developed to measure leukemia cell deformability, I found that leukemia cells taken from patients with leukostasis were significantly stiffer than leukemia cells taken from asymptomatic patients. To bring single-cell deformability measurements towards more clinical use, I developed a high-throughput microfluidic device to quantify cell deformation through capillary-like microchannels, which is referred to as biophysical flow cytometry. Leukemia cells from leukostasis patients had higher cell transit times and rates of microchannel occlusion than leukemia cells from asymptomatic patients. These results suggest that increased leukemia cell stiffness may be an independent leukostasis risk factor and could be useful for predicting and diagnosing leukostasis.
Using AFM and biophysical flow cytometry, I found that chemotherapy, the standard treatment for leukemia, increases leukemia cell stiffness by two orders of magnitude and therefore, may actually increase leukostasis risk. Toward therapies that reduce the risk associated with altered biophysical properties, I found that the phosphodiesterase inhibitor pentoxifylline substantially decreased leukemia cell stiffness and adhesiveness, and this drug may therefore be a possible therapy or prophylaxis for leukostasis. Overall, these studies show that cell mechanics - and alterations thereof - are relevant in disease pathophysiology. In addition, tools that measure cell mechanics are useful diagnostic or drug discovery platforms for predicting and treating disease states such as leukostasis in acute leukemia.