Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes—Basic and Translational Studies: Spliceosome-Mutant MDS
To test this hypothesis, we crossed Cre-based conditional Runx1 knockout mice (Runx1f/f) with mice carrying a newly developed Cre-based conditional U2af1-S34F mutation (U2af1+/S34F) to generate Runx1f/f, Mx1-Cre, U2af1+/S34F mice, which express U2af1-S34F and deficient-Runx1 after inducing Cre from the Mx1 promoter with poly (I:C). We found that U2af1-S34F attenuated the Runx1-/--induced increase of myeloid cells in spleen and bone marrow, as well as the increase of progenitor (lineage-/Sca1-/C-kit+) and stem cells (lineage-/Sca1-/C-kit+). Competitive repopulation assays showed that combining the U2af1 mutation and Runx1 deficiency impaired the transplantation capacity of bone marrow progenitor cells, especially for the myeloid lineage. We further aged these mice to examine the cooperative effects of U2af1-S34F and Runx1 deficiency in disease progression, upon the treatment of a one time, low-dose N-ethyl-N-nitrosourea. Mx1-Cre, U2af1+/S34F mice didn’t show survival defect when compared to control mice, while the Runx1f/f, Mx1-Cre mice developed MDS, as previously reported. Interestingly, of fourteen Runx1f/f, Mx1-Cre, U2af1+/S34F mice, two developed AML, and the rest developed MDS. Moreover, transplanted spleen and bone marrow cells from one of four MDS Runx1f/f, Mx1-Cre, U2af1+/S34F mice also developed AML in the recipients. Although Runx1f/f, Mx1-Cre mice also had MDS, their MDS cells did not develop into leukemia after transplantation. Our data therefore suggest that Runx1 deficiency and MDS-associated U2af1 mutation can cooperate in the genesis of AML from MDS.
Disclosures: No relevant conflicts of interest to declare.
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