Exploiting the Notch pathway in HTLV-1-driven adult T-cell leukemia/lymphoma: a mini-review.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and several inflammatory disorders. Despite extensive research, the molecular mechanisms underlying HTLV-1 pathogenesis remain incompletely defined. Among host pathways hijacked by the virus, Notch signaling has emerged as a critical regulator of T-cell biology, immune evasion, and leukemogenesis. The Notch family, comprising four receptors (NOTCH1-4) and five ligands (Jagged1/2, DLL1/3/4), regulates key cellular processes, including proliferation, differentiation, and survival. Evidence suggests that HTLV-1 proteins, such as Tax and HBZ, directly or indirectly modulate Notch activity, leading to the constitutive activation of the Notch pathway and oncogenic transformation. Mutations in NOTCH1 and FBXW7 further stabilize the Notch intracellular domain (NICD), sustaining the transcription of proliferative and anti-apoptotic genes. Recent studies also highlight the involvement of JAG1 overexpression, H19/miR-675-mediated regulation, and crosstalk with PI3K and STAT3 signaling in maintaining Notch-driven leukemic phenotypes. Preclinical findings demonstrate that inhibition of Notch through γ-secretase inhibitors, restoration of FBXW7 function, or blockade of ligand-receptor interactions reduces ATLL cell growth and leukemia-initiating cell populations. However, clinical trials with selective Notch inhibitors show limited efficacy, underscoring the complexity of targeting this pathway. This mini-review provides an overview of Notch signaling in HTLV-1 infection, its contribution to ATLL pathogenesis, and therapeutic opportunities. Understanding the receptor-specific roles and molecular interactions within the Notch cascade may offer novel avenues for targeted interventions in HTLV-1-associated malignancies.