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

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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Hayashi Y, Zhang Y, Yokota A, Yan X, Liu J, Choi K, Li B, Sashida G, Peng Y, Xu Z, Huang R, Zhang L, Freudiger GM, Wang J, Dong Y, Zhou Y, Wang J, Wu L, Bu J, Chen A, Zhao X, Sun X, Chetal K, Olsson A, Watanabe M, Romick-Rosendale LE, Harada H, Shih LY, Tse W, Bridges JP, Caligiuri MA, Huang T, Zheng Y, Witte DP, Wang QF, Qu CK, Salomonis N, Grimes HL, Nimer SD, Xiao Z, Huang G