Date of Award
Winter 2025
Project Type
Dissertation
Program or Major
Biochemistry
Degree Name
Doctor of Philosophy
First Advisor
Sherine Elsawa
Second Advisor
Omid Tavana
Third Advisor
Sarah Walker
Abstract
Waldenström Macroglobulinemia (WM) is a rare lymphoplasmacytic disease that is hallmarked by B-cell infiltration of the bone marrow, an overexpression of IgM class antibodies, and an activating mutation of MYD88 (L265P). The therapeutic options for WM patients include a combination of Rituximab (anti-CD20 monoclonal antibody) and chemotherapy, with newer treatments like proteasomal inhibitors and Bruton’s Tyrosine Kinase (BTK) inhibitors showing high levels of success both as monotherapy and in combinations. To date, WM remains incurable. Understanding the basic physiology of WM and creating new and improved pre-clinical models which better reflect the true physiology of WM will allow for the identification of novel therapeutic vulnerabilities and the ability to test these next generation therapies, both in a tumor intrinsic and extrinsic manner. In this study we explored the effects of BTK inhibitors on WM cell line models. The three cell line models were also characterized using RNA-seq and cytokine proteomic arrays with and without BTK inhibitor treatment. The chemokines CCL3 and CCL4 were modulated with BTK inhibitor treatment in all cell lines pointing toward an effect on macrophage chemotaxis. Secretion of CCL3 and CCL4 is partially regulated by the BTK-MEK1/2-ERK1/2 signaling pathway. The decrease and chemokine secretion caused by BTK inhibitors was sufficient to lower macrophage migration in a trans-well assay pointing towards a novel immunoregulatory function for BTK inhibitors in WM. Co-culture of M0, M1, and M2 macrophages with MWCL-1 cells yielded activation of both cell types measured by CD80 and CD86 levels, with M0 and M2 macrophages showing a trend toward increased CD163 levels in co-culture vs monoculture and acalabrutinib treatment showed a trend toward lowering levels of CD86 and CD206 in both populations. Neither treatment nor co-culture influenced the M1 population, although the M1 macrophages increased CD80 on the MWCL-1 cells. These effects point toward MWCL-1 cells increasing immunosuppressive markers in both M0 and M2 co-cultures while treatment lowered activation levels in the macrophages. In summary BTK inhibitors are having a significant non-cytotoxic effect on WM cell lines that can have major effects on the tumor microenvironment pointing towards a new mechanism of efficacy for BTK inhibitors in WM.
Recommended Citation
Blackmore, Stephen, "The Effects of Bruton's Tyrosine Kinase Inhibitors on Waldenstrom Macroglobulinemia" (2025). Doctoral Dissertations. 2978.
https://scholars.unh.edu/dissertation/2978