Death induction by CD99 ligation in TEL/AML1-positive acute lymphoblastic leukemia and normal B cell precursors

Abstract

Our study was performed to examine the role of CD99 in normal and leukemia BCPs. CD99 is strongly expressed by certain pediatric cancers including BCP-ALL. Modulation of the antigen in ETs and T cells induces apoptosis, hence implicating CD99 as a potential target for anti-cancer therapy. However, nothing is known about these aspects in BCPs. We investigated BCP-ALL cases and normal BCP cells from pediatric BM for CD99 protein and RNA expression as well as for effects of CD99 modulation by mAb. Immunophenotypes, recovery, apoptosis, and aggregation were assessed. Flow cytometry, light microscopy, and qRT-PCR were used in our experiments. An association of CD99 expression levels with the cytogenetic background of pediatric BCP-ALLs was found. Highest CD99 levels were observed in hyperdiploid, followed by TEL/AML1 and random karyotype leukemias. CD99 ligation moderately induced cell death only in TEL/AML1 cases. Stroma cell contact mitigated this effect. Very immature normal BCPs were the most sensitive to CD99-mediated death induction. Type I CD99 mRNA was the main isoform in ALLs and was expressed differentially during BCP maturation. Our data suggest that clinical targeting of CD99 may be effective in BCP-ALL-bearing TEL/AML1 but also may elicit negative effects on normal B-lymphopoiesis. We consider our results as an indication that CD99 may play a physiologic role in the clonal deletion processes necessary for B-lymphoid selection.

CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

“…In contrast, when normal mesenchymal stem cells were transfected with EWS-FLI1, their susceptibility to CD99 ligation increased and p53 was reactivated. Similarly, c/pre-B leukemia blasts carrying the TEL/AML1 chimera were found to be more sensitive to CD99-induced cell death (44). These findings indicate that rapid and massive CD99-induced cell death may occur preferentially in an aberrant genetic background, when cells being forced to grow by oncogenetic stimuli could not recover stressful signals through cell-cycle exit and result more vulnerable, thus offering new fuel to support the therapeutic use of anti-CD99 dAbd C7 against EWS cells.…”

“…Notably, CD99 expression disappeared in tumors that were efficiently inhibited by dAbd C7. A possible bystander effect of anti-CD99 approaches is the induction of the HSP70 that may activate NK cells cytotoxicity contributing to tumor elimination (44). To verify any possible involvement of this pathway in the efficacy of anti-CD99 therapy, we have assessed whether CD99 ligation induced HSP70 S6).…”

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

“…The signaling mechanism of human CD99 is still unknown, despite the numerous studies describing its roles in various cellular responses, such as transmigration of leukocytes and activation, proliferation, and apoptosis of lymphocytes (22,(45)(46)(47)(48). In this study, we showed that CD99-derived agonistic ligands function as novel suppres- sors of fibronectin-mediated ␤1 integrin activation in human breast carcinoma cells and uncovered for the first time the underlying mechanism by which CD99 regulates ␤1 integrin activity.…”

“…CD99 is implicated in multiple cellular responses, including cell apoptosis, differentiation, transport of membrane proteins, and activation and proliferation of lymphocytes (18)(19)(20)(21)(22)(23). The physiological significance of CD99 engagement has been clearly shown by an essential role for CD99 in the regulation of the transendothelial migration (TEM) of immune cells (24)(25)(26).…”

Interaction of CD99 with Its Paralog CD99L2 Positively Regulates CD99L2 Trafficking to Cell Surfaces

“…An additional role of mCD99, implication in cell death, has been reported; mCD99 + cells were killed through the recognition of mCD99 by PILRb-expressing NK cells (39), and the ligation of mCD99 to the polymeric fusion protein PILR-FC induced apoptosis in immature thymocytes (40), as is implicated in apoptosis of thymocytes by hCD99 (41), Ewing sarcoma cells (42,43), and lymphoblast leukemia cells (44). Given the physiologic heterodimeric and homodimeric forms of mCD99, therefore, the identity of CD99 family dimers dominant on the cell surface under normal physiological conditions, during inflammation-induced diapedesis, or during apoptosis would be necessary to be defined to understand the biological relevance of CD99 oligomerization and, ultimately, the role of CD99 protein, and this is currently under investigation.…”