This report describes a Drosophila model used to characterize the role CNOT3 and other components of the CCR4-NOT complex in the development of T-cell acute lymphoblastic leukemia (T-ALL) and other cancers. The fly model was developed when CNOT3 emerged as a candidate tumor suppressor gene in whole exome sequencing of (T-ALL) patients. The CCR4-NOT complex contributes to regulation of RNA metabolism at all steps, including transcription, mRNA stability, and eventual degradation in the cytoplasm. There is a single gene orthologous to CNOT3 in Drosophila, Dmel\Not3, for which RNAi targeting constructs and an allele caused by insertional mutagenesis have been generated.
None of the human CCR4-NOT complex genes has been introduced into flies.
Like all invertebrates, flies lack cells analogous to the hematopoietic lymphoid lineage. However, based on the knowledge that activating mutations of NOTCH1 are frequently associated with T-ALL, a fly model in which the Notch ligand Dl is overexpressed in the developing eyes was used as a sensitized system to characterize the impact of Dmel\Not3 mutations. This emulates the multi-step progression of most cancers, including ALL. Dl overexpression in eyes results in slightly enlarged but otherwise normal-appearing eyes. Dl overexpression combined with knockdown of Not3, effected by RNAi, results in dramatic hyperproliferative eye phenotypes.
Other subunits of the Drosophila CCR4-NOT complex have been tested in this system. Reduction in expression of Not1 (orthologous to human CNOT1), Rga (orthologous to CNOT2), or Pop2 (orthologous to CNOT7 and CNOT8) in combination with Dl overexpression results in hyperproliferative eye phenotypes. Reduction in expression of twin (orthologous to CNOT6 and CNOT6L) in combination with Dl overexpression results in metastatic, as well as hyperproliferative, phenotypes. Physical and genetic interactions have been described for these fly genes; see below and in the respective gene reports.
See also the human disease model report 'cancer, multiple, Notch signaling pathway' (FBhh0000766).
[updated Dec. 2018 by FlyBase; FBrf0222196]