Low Notch-1 and High Jagged-1 Expressions are Associated with Better Treatment Response and Survival in Adult Egyptian Patients with Acute Myeloid Leukemia
Noha Yousef Amin
Department of Clinical Pathology, Faculty of Medicine, Tanta University, Egypt.
Noha Elsayed Esheba
Department of Internal Medicine, Faculty of Medicine, Tanta University, Egypt.
Gamal Elsayed Khedr
Department of Clinical Pathology, Tanta Cancer Institute, Egypt.
Amany Mohamed Abo El-Enein
Department of Clinical Pathology, Faculty of Medicine, Tanta University, Egypt.
Sahar Ahmed Hamouda
Department of Clinical Pathology, Faculty of Medicine, Tanta University, Egypt.
*Author to whom correspondence should be addressed.
Abstract
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.
Keywords: Leukemia, AML, notch, flow cytometry