Contributions
Abstract: S134
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00
Location: Room N103
Background
Aims
Methods
We used CRISPR/Cas9-mediated mutagenesis to interfere with the MLL/SET complex in myeloid progenitor cells from a Cebpap30/p30 AML mouse model. Cellular competition assays were used to assess changes in proliferative capacity of mutant cells. Further, MLL activity was inhibited by the use of small molecules that block the Menin-MLL interaction. In both cases, proliferation, myeloid differentiation and apoptosis were used as readouts. Global changes in gene expression were measured by RNA-seq.
Results
We initially confirmed, via ChIP, that C/EBPα and MLL co-localize on the promoters of p30 target genes, indicating functional cooperativity in gene regulation.
Conclusion
We show that CEBPA-mutated AML is highly sensitive to perturbation of the MLL/SET complex, either via genetic ablation of MLL or through pharmacological inhibition of the Menin-MLL interaction. Our data indicate that leukemic mutations of C/EBPα selectively cooperate with the SET/MLL complex to regulate gene expression. These findings expand our understanding of and may inform new therapeutic strategies for N-terminal CEBPA mutated AML.
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemogenesis, Inhibitor, CCAAT/enhancer binding protein alpha (C/EBPa)
Abstract: S134
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00
Location: Room N103
Background
Aims
Methods
We used CRISPR/Cas9-mediated mutagenesis to interfere with the MLL/SET complex in myeloid progenitor cells from a Cebpap30/p30 AML mouse model. Cellular competition assays were used to assess changes in proliferative capacity of mutant cells. Further, MLL activity was inhibited by the use of small molecules that block the Menin-MLL interaction. In both cases, proliferation, myeloid differentiation and apoptosis were used as readouts. Global changes in gene expression were measured by RNA-seq.
Results
We initially confirmed, via ChIP, that C/EBPα and MLL co-localize on the promoters of p30 target genes, indicating functional cooperativity in gene regulation.
Conclusion
We show that CEBPA-mutated AML is highly sensitive to perturbation of the MLL/SET complex, either via genetic ablation of MLL or through pharmacological inhibition of the Menin-MLL interaction. Our data indicate that leukemic mutations of C/EBPα selectively cooperate with the SET/MLL complex to regulate gene expression. These findings expand our understanding of and may inform new therapeutic strategies for N-terminal CEBPA mutated AML.
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemogenesis, Inhibitor, CCAAT/enhancer binding protein alpha (C/EBPa)