posted on 2024-04-09, 15:20authored byMaria C. White, Jason P. Wong, Blossom Damania
Figure S1. Purity of primary B cells isolated from bulk PBMCs. (A) Flow cytometry analysis of primary B cell purity before (bulk PBMCs) and after (purified B cells) B cell purification from donor PBMCs using the STEMCELL EasySep system. Analyzed populations were gated on single cells and B cells were denoted as CD20-positive CD3-negative, while T cells were denoted as CD3-positive CD20-negative.
Funding
HHS | National Institutes of Health (NIH)
American Cancer Society (ACS)
History
ARTICLE ABSTRACT
Non–Hodgkin lymphoma (NHL) is a common cancer in both men and women and represents a significant cancer burden worldwide. Primary effusion lymphoma (PEL) is a subtype of NHL infected with Kaposi sarcoma–associated herpesvirus (KSHV). PEL is an aggressive and lethal cancer with no current standard of care, owing largely to its propensity to develop resistance to current chemotherapeutic regimens. Here, we report a reliance of KSHV-positive PEL on the mitotic kinase, NEK2, for survival. Inhibition of NEK2 with the inhibitor, JH295, resulted in caspase 3–mediated apoptotic cell death of PEL. Furthermore, NEK2 inhibition significantly prolonged survival and reduced tumor burden in a PEL mouse model. We also demonstrate that the ABC transporter proteins, MDR1 and MRP, are most active in PEL and that inhibition of NEK2 in PEL reduced the expression and activity of these ABC transporter proteins, which are known to mediate drug resistance in cancer. Finally, we report that JH295 treatment sensitized lymphomas to other chemotherapeutic agents such as rapamycin, resulting in enhanced cancer cell death. Overall, these data offer important insight into the mechanisms underlying PEL survival and drug resistance, and suggest that NEK2 is a viable therapeutic target for PEL.
The mitotic kinase, NEK2, is important for the survival of KSHV-positive PEL. NEK2 inhibition resulted in PEL apoptosis and reduced tumor burden in a mouse model. NEK2 inhibition also reduced drug resistance.