Following a similar report on multiple myeloma, Ghione and colleagues report the expected observation that patients with non-Hodgkin lymphoma (NHL) receiving anti-B cell therapies have markedly reduced antibody responses to COVID-19 immunization. Although there is no information regarding T-cell immunity, this suggests that while vaccination is certainly still recommended for this population, patients should be strongly encouraged to maintain social distancing precautions and should be revaccinated after an appropriate interval from the end of their antilymphoma therapy.

The serine/threonine kinase, PIM1, is involved in promoting cell survival in part by phosphorylation and inhibition of proapoptotic proteins. ASK1, a mitogen-activated protein kinase kinase kinase (MAPKKK), is involved in the so-called stress-activated pathways that contribute to apoptotic cell death. Here we show that PIM1 phosphorylates ASK1 specifically on serine residue 83 (Ser83) both in vitro and in vivo and that PIM1 binds to ASK1 in cells by co-immunoprecipitation. Using H1299 cells, our results further demonstrate that PIM1 phosphorylation of ASK1 decreases its kinase activity induced by oxidative stress. PIM1 phosphorylation of ASK1 on Ser83 inhibited ASK1-mediated c-Jun N-terminal kinase (JNK) phosphorylation as well as phosphorylation of p38 kinase. Under H2O2-induced stress conditions that normally lead to apoptosis, these phosphorylation events were associated with inhibition of caspase-3 activation and resulted in reduced cell death. Moreover, knockdown of PIM1 in H1299 cells decreased phosphorylation of endogenous Ser83 of ASK1 and was associated with a decrease in cell viability after H2O2 treatment. Taken together, these data reveal a novel mechanism by which PIM1 promotes cell survival that involves negative regulation of the stress-activated kinase, ASK1.

Our data suggest that vorinostat is active in RRCL with a known defective apoptotic machinery, it can active alternative cell death pathways. Given the multiple pathways affected by HDAC inhibition, vorinostat can potentially be used to overcome acquired resistant to chemotherapy in aggressive B cell lymphoma.

Pim-2 kinase is one of three highly conserved Pim family members which are known to be involved in cell survival and cell proliferation. Here we demonstrate that like Pim-1, Pim-2 also phosphorylates the cell cycle inhibitor p21 Cip1/WAF1 (p21) on Thr145 in vitro and in vivo. Overexpression of Pim-2 in HCT116 cells leads to the increased stability of p21, and results in enhanced levels of both exogenous and endogenous p21 proteins. Knock-down of Pim-2 expression via siRNA results in reduced level of endogenous p21, indicating that like Pim-1, Pim-2 is another legitimate p21 kinase. However, Pim-2 has no influence on the nuclear localization of p21 in HCT116 cells. In addition, Pim-2 is able to arrest the cell cycle at G1/S phase and inhibit cell proliferation through phosphorylation of p21 in HCT116 cells. These data suggest that Pim-2 phosphorylation of p21 enhances p21's stability and inhibits cell proliferation in HCT116 cells.

In order to identify cellular pathways associated with therapy-resistant aggressive lymphoma, we generated rituximab-resistant cell lines (RRCL) and found that the acquirement of rituximab resistance was associated with a deregulation in glucose metabolism and an increase in the apoptotic threshold leading to chemotherapy resistance. Hexokinase II (HKII), the predominant isoform overexpressed in cancer cells, has dual functions of promoting glycolysis as well as inhibiting mitochondrialmediated apoptosis. We found that RRCL demonstrated higher HKII levels. Targeting HKII resulted in decreased mitochondrial membrane potential, ATP production, cell viability; and re-sensitization to chemotherapy agents. Analyzed gene expression profiling data from diffuse large B-cell lymphoma patients, high-HKII levels were associated with a shorter progression free survival (PFS) and/or overall survival (OS). Our data suggest that over-expression of HKII is associated with resistance to rituximab and chemotherapy agents in aggressive lymphoma and identifies this enzyme isoform as a potential therapeutic target. www.impactjournals.com/oncotarget/