Contributions
Abstract: S125
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00
Location: Room N101
Background
Recurrent somatic mutations of N-terminal region of FOXO1, shown previously to increase FOXO1 nuclear localization and activity, have been linked to diminished survival in DLBCL patients uniformly treated with rituximab-based immunotherapy. Although the contribution of FOXO1 mutations to the therapeutic resistance of B-NHLs becomes apparent, the molecular mechanism underlying this phenomenon has not been explained so far. The diminished levels of CD20 on the cell surface of tumor cells are among several potential mechanisms underlying the resistance to treatment with anti-CD20 monoclonal antibodies.
Aims
We have recently reported that the tonic BCR signaling activates FOXO1, and that inhibitors of the downstream BCR signaling pathways downregulate CD20 expression. Therefore, here we sought to determine whether FOXO1 might regulate the abundance of CD20 on the surface of tumor cells thus influencing the response to rituximab-based therapies.
Methods
We used CRISPR/Cas9 genome editing technology and lentiviral transduction to study the role of FOXO1 protein in CD20 regulation. qRT-PCR and Dual Luciferase Assays was done to determine the influence of FoXO1 on CD20 transcription. To get insight into molecular interaction between FOXO1 and CD20 promoter we performed EMSA and ChIP experiments. For animal studies we used SCID Fox Chase mice model. All in vivo experiments were carried out at the animal facility of The Francis Crick Institute in accordance with the guidelines and were approved by the Ethics Committee.
Results
Conclusion
Session topic: 18. Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): Rituximab, lymphoma, CD20
Abstract: S125
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00
Location: Room N101
Background
Recurrent somatic mutations of N-terminal region of FOXO1, shown previously to increase FOXO1 nuclear localization and activity, have been linked to diminished survival in DLBCL patients uniformly treated with rituximab-based immunotherapy. Although the contribution of FOXO1 mutations to the therapeutic resistance of B-NHLs becomes apparent, the molecular mechanism underlying this phenomenon has not been explained so far. The diminished levels of CD20 on the cell surface of tumor cells are among several potential mechanisms underlying the resistance to treatment with anti-CD20 monoclonal antibodies.
Aims
We have recently reported that the tonic BCR signaling activates FOXO1, and that inhibitors of the downstream BCR signaling pathways downregulate CD20 expression. Therefore, here we sought to determine whether FOXO1 might regulate the abundance of CD20 on the surface of tumor cells thus influencing the response to rituximab-based therapies.
Methods
We used CRISPR/Cas9 genome editing technology and lentiviral transduction to study the role of FOXO1 protein in CD20 regulation. qRT-PCR and Dual Luciferase Assays was done to determine the influence of FoXO1 on CD20 transcription. To get insight into molecular interaction between FOXO1 and CD20 promoter we performed EMSA and ChIP experiments. For animal studies we used SCID Fox Chase mice model. All in vivo experiments were carried out at the animal facility of The Francis Crick Institute in accordance with the guidelines and were approved by the Ethics Committee.
Results
Conclusion
Session topic: 18. Non-Hodgkin & Hodgkin lymphoma - Biology
Keyword(s): Rituximab, lymphoma, CD20