Physical contact with endothelial cells through β1- and β2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells

Background

Chronic lymphocytic leukemia B cells display prolonged survival in vivo, but when cultured in vitro rapidly undergo spontaneous apoptosis. We hypothesize that interactions with endothelial cells in infiltrated tissues and during recirculation may have a pathogenic role in chronic lymphocytic leukemia.

Design and Methods

We evaluated apoptosis of leukemic cells after co-culture on a monolayer of human umbilical vein endothelial cells with addition of fludarabine and antibodies that block adhesion. Then, we compared microarray-based gene expression profiles between leukemic cells at baseline and after co-culture.

Results

We found that the endothelial layer protected leukemic cells from apoptosis inducing a 2-fold mean decrement in apoptotic cells after 2 days of co-culture. Moreover, the endothelial layer decreased the sensitivity of chronic lymphocytic leukemia B cells to fludarabine-induced apoptosis. Physical contact with endothelium mediated by both β₁- and β₂- integrins is essential for the survival advantage of leukemic cells. In particular, blocking CD106 on endothelial cells or CD18 on leukemic B cells led to the almost complete abrogation of the survival advantage (>70% inhibition of viability). However, a reduction of apoptosis was also measured in leukemic cells cultured in conditioned medium collected after 2 days of co-culture, implying that survival is partially mediated by soluble factors. Overall, the contact with endothelial cells modulated 1,944 genes in chronic lymphocytic leukemia B cells, establishing a peculiar gene expression profile: up-regulation of angiogenesis-related genes, an increase of genes involved in TGFβ and Wnt signaling pathways, secretion of cytokines recruiting stromal cells and macrophages and up-regulation of anti-apoptotic molecules such as Bcl2 and Survivin.

Conclusions

Our study supports the notion that endothelial cells are major players in the chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly supports survival, protects from drug-induced apoptosis and extensively modifies the gene expression profile of leukemic cells.     

Posterior Reversible Encephalopathy Syndrome Following a Scorpion Sting

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity not yet understood, that is present with transient neurologic symptoms and particular radiological findings. The most common imaging pattern in PRES is the presence of edema in the white matter of the posterior portions of both cerebral hemispheres. The cause of PRES is unclear. We report a case of 13‐year‐old male who was stung by a scorpion and developed a severe headche, visual disturbance, and seizures and had the diagnosis of PRES with a good outcome. Numerous factors can trigger this syndrome, most commonly: acute elevation of blood pressure, abnormal renal function, and immunosuppressive therapy. There are many cases described showing the relationship between PRES and eclampsia, transplantation, neoplasia and chemotherapy treatment, systemic infections, renal disease acute, or chronic. However, this is the first case of PRES following a scorpion sting.     

Are we ready for definitive clinical guidelines on xylitol/polyol use?

In the past decades, numerous studies have looked at the anticaries effects of polyols, particularly xylitol, and a great many studies have focused on xylitol's antimicrobial properties. Researched vehicles have mostly included chewing gums, followed by lozenges/candies, toothpastes, and others (e.g., syrup). Good evidence supports the claims that xylitol is non-cariogenic and has a dose-/frequency-dependent antimicrobial effect on dental plaque/mutans streptococci, and that polyol use is very safe. However, interpretation of caries data has been controversial, due in part to variability in study designs, formulations/dosages tested, and outcomes reported (e.g., many caries studies have a "no gum" control, limiting the interpretation of the polyol's benefit; few studies have compared different polyols side-by-side, or in adults). Even when the level/strength of high-quality anticaries evidence is still limited, most recent systematic reviews have consistently concluded that the habitual use of sucrose-free xylitol or polyol-combination chewing gum/ lozenges is an effective adjunct in coronal caries prevention. Consequently, many health organizations worldwide are supporting this recommendation for at-risk populations. However, most experts agree that well-designed, placebo-controlled randomized clinical trials (RCTs) (focusing on efficacy, feasibility, adherence, dosage, vehicle, synergism with other preventive strategies, and cost) are still needed in target populations worldwide to reach definitive caries-preventive/therapeutic recommendations.