Notch signaling in leukemia.
Mammalian Notch homologs were first identified from the involvement of Notch1 in a recurrent chromosomal translocation in a subset of human T-cell leukemias. The effect of the translocation was twofold: Notch expression was placed under the control of a T-cell-specific element, and Notch was truncated, resulting in a constitutively active protein. Subsequent work has shown that Notch1 is required for T cell commitment and is exclusively oncotropic for T cells. During the past year, several murine models have been used to dissect the function of Notch signaling in lymphoid development and leukemia. These models show that Notch1 drives the earliest stages of T cell commitment and that Notch signaling must be downregulated by the double positive stage for proper T cell development to occur. Constitutive Notch signaling mediated by Notch1, Notch2, or Notch3 predisposes to T-cell leukemia. Future studies are expected to elucidate the mechanisms by which Notch leads to transformation. Identification of the transcriptional targets of Notch signaling is likely to yield important insights.
Aster
J C
JC
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Pear
W S
WS
D000818:Animals; D002471:Cell Transformation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D007942:Leukemia, Experimental / Q000209:etiology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology*; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors
D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors