Molecular pathogenesis and targeted therapies for NOTCH1-induced T-cell acute lymphoblastic leukemia

作者：Paganin Maddalena; Ferrando Adolfo^*

来源：Blood Reviews, 2011, 25(2): 83-90.

DOI：10.1016/j.blre.2010.09.004

• T-ALL
• NOTCH
• Gamma-secretase inhibitors
• Targeted therapy
• Prognosis
• Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor resulting from the malignant transformation of immature T-cell progenitors. Originally associated with a dismal prognosis, the outcome of T-ALL patients has improved remarkably over the last two decades as a result of the introduction of intensified chemotherapy protocols. However, these treatments are associated with significant acute and long-term toxicities, and the treatment of patients presenting with primary resistant disease or those relapsing after a transient response remains challenging.
T-ALL is a genetically heterogeneous disease in which numerous chromosomal and genetic alterations cooperate to promote the aberrant proliferation and survival of leukemic lymphoblasts. However, the identification of activating mutations in the NOTCH] gene in over 50% of T-ALL cases has come to define aberrant NOTCH signaling as a central player in this disease. Therefore, the NOTCH pathway represents an important potential therapeutic target. In this review, we will update our current understanding of the molecular basis of T-ALL, with a particular focus on the role of the NOTCH1 oncogene and the development of anti-NOTCH1 targeted therapies for the treatment of this disease.

• 出版日期2011-3