HAPLOINSUFFICIENCY OF TIE2 IN MUTATED BLOOD CELLS SUPPRESS ANGIOGENESIS IN THE BONE MARROW AND INHIBIT PROGRESSION OF MDS

Abstract

Introduction: Tie2 is a receptor tyrosine kinase and regulates angiogenesis and vascular quiescence. Given that Tie2 modulates microvascular density in cancer, we hypothesized that deletion of Tie2 in blood cells can inhibit progression of myelodysplastic syndrome (MDS). We attempted to understand the role of Tie2 in development of MDS by using an Ezh2/Tet2 double knock out (DKO) mouse model. Methods: We transplanted bone marrow (BM) cells isolated from Cre-ERT2 mice, Tie2flox/wt; Cre-ERT2 mice, Ezh2flox/flox; Tet2flox/flox; Cre-ERT2 mice, Ezh2flox/flox; Tet2flox/flox; Tie2flox/wt; Cre-ERT2 mice and Ezh2flox/flox; Tet2flox/flox; Tie2flox/flox; Cre-ERT2 mice into lethally-irradiated Ly5.1+ recipient mice. Ezh2, Tet2 and Tie2 genes were deleted by administration of tamoxifen one month post the transplantation. Results: We found that Ezh2−/−Tet2−/- DKO, Ezh2−/−Tet2−/- Tie2+/− (DKOTie2+/−) and Ezh2−/−Tet2−/- Tie2−/− TKO mice all developed MDS and MDS/MPN, showing anemia and dysplastic cells in the peripheral blood (PB) and the BM; however, DKOTie2+/− mice showed significantly longer survival than did DKO mice and TKO mice. While DKO mice showed deformed CD31+ endothelial cells and increased vascular density in the BM, DKOTie2+/− mice mitigated the altered vascular formation in the BM. RNA-sequencing revealed that DKOTie2+/− stem cells repressed expression of genes involved in interferon, cell cycles and angiogenesis, compared to DKO stem cells, suggesting that the haploinsufficiency of Tie2 impaired the property of MDS cells to drive angiogenesis in the BM, resulting in the delayed development of MDS. Conclusions: We are now working on the molecular mechanism of how the Tie2 gene in blood cells modulates the angiogenesis to drive the progression of MDS.