Journal
CURRENT OPINION IN HEMATOLOGY
Volume 11, Issue 6, Pages 426-433Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.moh.0000143965.90813.70
Keywords
NOTCH signaling; T cell acute lymphoblastic leukemia/lymphoma
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Purpose of review Although 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 findings NOTCH1 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 -gamma-secretase, a protease required for normal NOTCH signal transcluction and the activity of the mutated forms of NOTCH1 found commonly in human T cell acute lymphoblastic leukemia/lymphoma. Summary These 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 gamma-secretase antagonists, in this aggressive human malignancy.
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