Low Notch-1 and High Jagged-1 Expressions are Associated with Better Treatment Response and Survival in Adult Egyptian Patients with Acute Myeloid Leukemia

Background: Acute Myeloid Leukemias (AMLs) are neoplastic proliferations arising in hematopoietic precursor cells in the bone marrow resulting in overgrowth of myeloblasts and other cells of myeloid lineage. Notch-1 receptor is a transmembrane protein of type I. Interactions between Notch-1 and its ligands Jagged-1 and Dll-1 result in proteolytic cleavages inside the receptor, followed by the release and nuclear translocation of the intracellular domain (Notch-1-IC). Notch-1 expression was also found in CD34+ bone marrow progenitors and other cells in peripheral blood and bone marrow. Jagged-1 and Delta-like1 (Dll-1) seem to be functionally opposing members of the Notch-1 ligand family; however, their precise methods of action in AML are unknown.

Methods: Using flow cytometry, the expression of the Notch-1 intracellular domain and the surface expression of Jagged-1 and Dll-1 ligands on leukemic blasts from newly diagnosed AML patients was evaluated. In addition, protein expression was associated with clinical data, laboratory data, responsiveness to therapy, Disease-Free (DFS) and Overall Survival (OS).

Results: Notch-1 was positively expressed in 20% of studied patients. Positive Notch-1 expression was associated with shorter OS (6.1 months) and DFS (3.1 months). Higher Notch-1 expression levels were significantly associated with lower remission and higher relapse rates. In contrary, Jagged-1 protein marker weas positively expressed in 56% studied patients, those patients showed shorter OS (6.6 months) and longer DFS (3.6 months) compared to negatively expressed ones. Higher Jagged-1 expression levels were significantly associated with higher remission and lower relapse rates. Positive Dll-1 expression was recorded in 30 % patients, yet with no significant relationship with OS and DFS rates as well as clinical outcome after therapy.

Conclusion: Both Notch-1 receptor and its ligands, Jagged-1 and Dll-1, seem to be implicated in AML pathogenesis, however Jagged-1 has a greater impact on clinical findings than Dll-1. A better prognosis is related with high Jagged-1 surface expression in individuals with AML. Hence, further research is required to acquire a greater knowledge of the modes of action of Notch-1 and its ligands in AML.