Institute for Cancer Genetics.
Department of Pathology, and.
Blood. 2017 Mar 2;129(9):1124-1133. doi: 10.1182/blood-2016-09-692582. Epub 2017 Jan 23.
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 gene, has emerged as a major regulator of leukemia cell growth and metabolism. T-ALL 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 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.
T 细胞急性淋巴细胞白血病（T-ALL）是一种高度增殖性血液恶性肿瘤，源于不成熟 T 细胞前体的转化。T-ALL 淋巴母细胞中的异常细胞生长和增殖是由激活促进细胞合成代谢和细胞周期进展的强致癌驱动因素维持的。在超过 65%的 T-ALL 患者中，NOTCH 信号通路被基因中的激活突变激活，已成为白血病细胞生长和代谢的主要调节剂。T-ALL 突变导致配体非依赖性和持续的 NOTCH1 受体信号转导，进而激活以参与合成代谢途径的基因上调为主导的广泛转录程序。在这些基因中，癌基因在 NOTCH1 诱导的转化中起主要作用。因此，NOTCH1 在 T-ALL 中的致癌活性严格依赖于 MYC 的上调，这使得 NOTCH1-MYC 调控回路成为治疗 T-ALL 的一个有吸引力的治疗靶点。
