T cell acute lymphoblastic leukemia/lymphoma: a human cancer commonly associated with aberrant NOTCH1 signaling


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Abstract

Purpose of reviewAlthough constitutively activated forms of the NOTCH1 receptor are potent inducers of T cell acute lymphoblastic leukemia/lymphoma when expressed in the bone marrow stem cells of mice, the known involvement of NOTCH1 in human T cell acute lymphoblastic leukemia/lymphoma has been restricted to very rare tumors associated with a (7;9) chromosomal translocation involving the NOTCH1 gene. This picture has changed dramatically in the past year with the discovery of frequent mutations involving NOTCH1 in human T cell acute lymphoblastic leukemia/lymphoma.Recent findingsNOTCH1 point mutations, insertions, and deletions producing aberrant increases in NOTCH1 signaling are frequently present in both childhood and adult T cell acute lymphoblastic leukemia/lymphoma and are detected in tumors from all major molecular subtypes. These observations are particularly important in the light of experiments using human and murine T cell acute lymphoblastic leukemia/lymphoma cell lines indicating that NOTCH1 signals are required for sustained growth and, in a subset of lines, survival. This inference is based in part on experiments conducted with small molecule inhibitors of γ-secretase, a protease required for normal NOTCH signal transduction and the activity of the mutated forms of NOTCH1 found commonly in human T cell acute lymphoblastic leukemia/lymphoma.SummaryThese findings support a central role for aberrant NOTCH signaling in the pathogenesis of human T cell acute lymphoblastic leukemia/lymphoma, and they provide a rationale for trials of NOTCH inhibitors, such as γ-secretase antagonists, in this aggressive human malignancy.

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