Abstract
In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels of the anti-apoptotic protein Mcl-1. Thus, Notch signaling promotes CLL cell survival at least in part by sustaining Mcl-1 expression. In CLL cells, an enhanced Notch activation also contributes to the increase in Mcl-1 expression and cell survival induced by IL-4.Mcl-1 downregulation by Notch targeting is not due to reduced transcription or degradation by caspases, but in part, to increased degradation by the proteasome. Mcl-1 downregulation by Notch targeting is also accompanied by reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), suggesting that this protein is another target of Notch signaling in CLL cells.Overall, we show that Notch signaling sustains CLL cell survival by promoting Mcl-1 expression and eIF4E activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL.
Highlights
Notch signaling is involved in various cellular processes, including cell fate specification, differentiation, proliferation, and apoptosis
We show that Notch signaling sustains chronic lymphocytic leukemia (CLL) cell survival by promoting Mcl-1 expression and eukaryotic initiation factor 4E (eIF4E) activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL
These results suggest that NOTCH1 mutation does not influence the sensitivity of CLL cells to Notch targeting, at least when it is harboured by a small fraction of leukemic cells, as indicated by the low NOTCH1 mutant allele burden detected in all three mutated samples examined (Table 1)
Summary
Notch signaling is involved in various cellular processes, including cell fate specification, differentiation, proliferation, and apoptosis. Abnormal Notch signaling is oncogenic in several cancers, including hematologic malignancies [1]. Disregulated Notch signaling has been associated with chronic lymphocytic leukemia (CLL), a frequent adult leukemia characterized by the accumulation of CD19+/CD5+ B lymphocytes resistant to apoptosis [2]. Notch signaling contributes to apoptosis resistance in CLL underscores the importance of Notch in this leukemia [8, 9], encouraging further investigation of its therapeutic potential. A better understanding of the mechanisms involved in the anti-apoptotic signaling of Notch in CLL cells may provide insight for designing future Notch-targeted therapies
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