HDAC inhibitors repress Tek and Angpt1 expression and proliferation in RUNX1-MECOM-type leukemia cells

Abstract

The RUNX1-MECOM fusion gene generated by the t(3;21)(q26;q22) translocation is a causative gene of acute megakaryoblastic leukemia, and the generated product performs various molecular functions by recruiting histone deacetylase (HDAC). We had previously established a mouse bone marrow transplantation model through the retroviral transduction of RUNX1-MECOM. This model demonstrated that RUNX1-MECOM-expressing cells developed acute megakaryoblastic leukemia and were serially transplantable. Gene expression analyses using quantitative RT-PCR arrays revealed that Angpt1 (Angiopoietin 1) and Tek transcripts were elevated in the leukemic cells. In this study, we confirmed the concomitant expression of Angpt1 and Tek proteins in the RUNX1-MECOM-expressing cells. When the primary leukemic cells were stimulated with exogenous Angpt1, endogenous Tek was phosphorylated, followed by the phosphorylation of downstream Akt. Angpt1 and Tek may form a circuit of an autocrine loop and enhance leukemia cell survival. Interestingly, the expression of Tek and Angpt1 was downregulated by HDAC inhibitors (HDACi), trichostatin A (TSA) and valproic acid (VPA). Therefore, HDACi may block the Angpt1 and Tek autocrine loop. Both TSA and VPA inhibited the growth of RUNX1-MECOM-expressing cells in vitro by inducing cell cycle arrest and apoptosis. Electron microscopic analysis further indicated that partial megakaryocytic differentiation was induced after HDACi treatment. Furthermore, intraperitoneal injection with VPA, but not TSA, extended the survival of the secondary transplanted mice. These data demonstrate the potential of HDACi as a promising targeted treatment for RUNX1-MECOM-type leukemia.