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Accession IconSRP089915

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

Organism Icon Mus musculus
Sample Icon 4 Downloadable Samples
Technology Badge IconIllumina HiSeq 1000

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Description
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-1a in this model, we also generated MllPTD/WT/Runx1Flox/Flox/Hif-1aFlox/Flox/Mx1-Cre mice and genetically eliminated Hif-1a expression. We analyzed gene expression variations in the HSPCs comparing the MllPTD/WT/Runx1?/? with or without HIF-1a abrogation. Overall design: Expression profiles of mRNA in HSPCs from MLL-PTD/Runx1-KO mice with or without HIF-1a
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