PLX249988

GSE86953: MLL-PTD and RUNX1-knockout cooperate to induce MDS phenotypes

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

The MLL-PTD mutation is found in patients with MDS and AML, and not in other hematological malignancies. Previously, we showed that Mll-PTD knock-in heterozygous mice (MllPTD/WT mice) present with several MDS-associated features. However, these phenotypes are insufficient to constitute bona fide MDS. MllPTD/WT mice do not generate MDS or AML in primary or transplant recipient mice. This suggests that additional genetic and/or epigenetic defects are necessary for transformation to MDS or AML. In secondary AML and de novo AML, MLL-PTD mutation is significantly associated with mutations in RUNX1 and with the FLT3-ITD mutations. In fact, the combination of MLL-PTD with the FLT3-ITD allele leads to AML in mice. We combined the MLL-PTD with RUNX1 mutant proteins, in order to generate a new mouse model for MDS. We generated MllPTD/WT/Runx1Flox/Flox/Mx1-Cre mice to model loss-of-function RUNX1 mutations. To test the significance of HIF-1 in this model, we also generated MllPTD/WT/Runx1Flox/Flox/Hif-1Flox/Flox/Mx1-Cre mice and genetically eliminated Hif-1 expression. We analyzed gene expression variations in the HSPCs comparing the MllPTD/WT/Runx1/ with or without HIF-1 abrogation. SOURCE: Nathan Salomonis (nathan.salomonis@cchmc.org) - Nathan Salomonis Cincinnati Children's Hospital