XB-ART-52805Oncotarget. December 27, 2016; 7 (52): 86889-86901.
VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice.
Homeobox genes are key regulators in normal and malignant hematopoiesis. The human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus laevis Xvent-2 gene, was shown to be highly expressed in normal myeloid cells and in patients with acute myeloid leukemia. We now demonstrate that constitutive expression of VENTX suppresses expression of genes responsible for terminal erythroid differentiation in normal CD34+ stem and progenitor cells. Transplantation of bone marrow progenitor cells retrovirally engineered to express VENTX caused massive expansion of primitive erythroid cells and partly acute erythroleukemia in transplanted mice. The leukemogenic potential of VENTX was confirmed in the AML1-ETO transplantation model, as in contrast to AML1-ETO alone co-expression of AML1-ETO and VENTX induced acute myeloid leukemia, partly expressing erythroid markers, in all transplanted mice. VENTX was highly expressed in patients with primary human erythroleukemias and knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked cell growth. In summary, these data indicate that VENTX is able to perturb erythroid differentiation and to contribute to myeloid leukemogenesis when co-expressed with appropriate AML oncogenes and point to its potential significance as a novel therapeutic target in AML.
PubMed ID: 27888632
PMC ID: PMC5349961
Article link: Oncotarget.
Genes referenced: gnl3 ptpn11 runx1
Article Images: [+] show captions
|Figure 1. A. Heatmap of differentially expressed genes as determined by RNA-seq between CD34+ CB cells overexpressing VENTX compared to the empty vector control (n=3). B. Differentially expressed genes transcription factors, which are known to play a role in erythroid development. ****: p<0.0001, ***: p≤0.0001, **: p≤0.001. C. Gene set enrichment analysis of genes involved in erythropoietic differentiation.|
|Figure 3. Cell proliferation in liquid expansion cultures from HEL cells after shRNA mediated knockdown of VENTX (shVENTX_73, shVENTX_77) compared to the scrambled control. Knockdown efficiency was 99% for both shRNA constructs (n=3).|
|Figure 5. A. Representative cytomorphological analysis of bone marrow cytospins of diseased mice as indicated (AE/VENTX 1° and 2°) compared to a representative non-leukemogenic AE 1° mouse. B. Representative flow cytometric analysis of a primary AE/VENTX recipient mouse (left side) and a secondary AE/VENTX recipient mouse (right side) C. Histological analysis of two secondary transplanted AE/VENTX mice, showing erythroblasts in the spleen of the diseased animals.|