Prognostic Impact of Notch Signaling in Acute Myeloid Leukemia (AML)

Background: Notch signaling is a developmental pathway involved in normal and malignant hematopoiesis. Mutations in Notch genes lead to T-ALL and are associated with poor prognosis in B-CLL. However its role in AML is still under investigation, with controversial results. In addition, although the pathway consists of 4 receptors and 5 ligands, many studies are mostly based on single receptor or ligand.

Aims: This study was conducted to determine if the expression level of each Notch receptor and ligand are associated with known prognostic factors and patient's survival.

Methods: AML primary cells were collected from 79 AML patients after informed consent. The follow-up was for 36 months. Flow cytometry analysis was used to study the expression of each Notch receptor and ligand. Prognostics or risk factors considered were sex, white blood counts, FAB and cytogenetics. The Mann-Whitney test was used for analyzing differences in expression levels between two groups. Spearman test was used for correlation between Notch expression levels and prognostics factors. Differences in overall (OS) and progression free (PFS) survival were established through Gehan-Breslow-Wilcoxon test.

Results: Consistently with previous findings, we found expression of Notch1, Notch2, Notch3, Notch4, Jagged1, Jagged2 and DLL3 in AML samples. There were no differences in expression levels between male and female. For each receptor or ligand, higher expression levels were found in more immature samples (M0, M1, and M2). Notch3, Notch4 and Jagged2 were enriched in adverse cytogenenetics risk groups compared to favorable cytogenetics risk patients. Then, for each receptor or ligand, patients were divided into two groups; patients with higher expression levels and patients with lower expression levels. Analyzing OS and PFS, we found that patients with lower expression levels of Notch4, Jagged2 and DLL3 displayed a longer survival compared to patients with higher expression levels.

Conclusion: Given its oncogenic role in T-ALL and other malignancies Notch1 has been the more studied receptors in hematological malignancies. However, we have previously demonstrated that Notch4, DLL3 and Jagged2 are all involved in survival of AML and B-ALL cells. Studying the prognostic value of all Notch receptors and ligands, the current research clearly shows that higher levels of Notch4 and Jagged2 are found in poor cytogenetics risk groups and are associated with a shorter patient's survival. These demonstrations suggest that expression levels of Notch receptors and ligands in AML patient's samples at diagnostic could stand as prognostic marker for clinical care.