Notch signaling in leukemia

Mammalian Notch homologs were first identified from the involvement of Notc h I in a recurrent chromosomal translocation in a subset of human T-cell le ukemias. The effect of the translocation was twofold: Notch expression was placed under the control of a T-cell-specific element, and Notch was trunca ted, resulting in a constitutively active protein. Subsequent work has show n that Notch1 is required for T cell commitment and is exclusively oncotrop ic for T cells. During the past year, several murine models have been used to dissect the function of Notch signaling in lymphoid development and leuk emia. These models show that Notch1 drives the earliest stages of T cell co mmitment and that Notch signaling must be downregulated by the double posit ive stage for proper T cell development to occur. Constitutive Notch signal ing mediated by Notch1, Notch2, or Notch3 predisposes to T-cell leukemia. F uture 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. (C) 2001 Lippincott Willia ms & Wilkins, Inc.