The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia

• Published in: Blood Vol. 129; no. 9; pp. 1124 - 1133
• Main Authors: Sanchez-Martin, Marta, Ferrando, Adolfo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.03.2017
• Subjects: Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Humans; Mutation; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-09-692582

T-cell acute lymphoblastic leukemia (T-ALL) is a highly proliferative hematologic malignancy that results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation in T-ALL lymphoblasts are sustained by activation of strong oncogenic drivers promoting cell anabolism and cell cycle progression. Oncogenic NOTCH signaling, which is activated in more than 65% of T-ALL patients by activating mutations in the NOTCH1 gene, has emerged as a major regulator of leukemia cell growth and metabolism. T-ALL NOTCH1 mutations result in ligand-independent and sustained NOTCH1-receptor signaling, which translates into activation of a broad transcriptional program dominated by upregulation of genes involved in anabolic pathways. Among these, the MYC oncogene plays a major role in NOTCH1-induced transformation. As result, the oncogenic activity of NOTCH1 in T-ALL is strictly dependent on MYC upregulation, which makes the NOTCH1-MYC regulatory circuit an attractive therapeutic target for the treatment of T-ALL.