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

Abstract

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 NOTCH1 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.

Figure 1. NOTCH1 mutations in T-ALL

Schematic representation of the NOTCH1 receptor structure and types of NOTCH1 mutations found in T-ALL. EGF-like, EGF-like repeats involved in ligand recognition. NRR, negative regulatory region. LNR, Lin12-NOTCH repeats. HD, heterodimerization domain. RAM, RAM domain. ANK, ankyrin repeats. TAD, transactivation domain. PEST, proline, glutamic acid, serine and threonine rich domain. ICN1, intracellular NOTCH1.