Abstract
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.
Highlights
It has been shown that early developmental genes play a major role in adult hematopoiesis including orchestrating self-renewal and differentiation of hematopoietic stem and progenitor cells
For this VENTX was retrovirally expressed in normal human CD34+ cord blood (CB) cells for 48h before performing RNA-sequencing (RNA-Seq) (n=3). 278 genes were differentially expressed between VENTX and the empty vector control (Supplementary Table S1, Figure 1A)
Gene set enrichment analysis focusing on genes known to be involved in erythroid differentiation showed a highly significant negative enrichment in VENTX overexpressing cells compared to the empty vector control (Figure 1C)
Summary
It has been shown that early developmental genes play a major role in adult hematopoiesis including orchestrating self-renewal and differentiation of hematopoietic stem and progenitor cells. This is exemplified by the family of homeobox genes, known to be key regulators in embryogenesis, and during normal postnatal hematopoiesis [1]. Constitutive expression of VENTX in normal CD34+ human progenitor cells impaired lymphoid engraftment and fostered generation of myeloid cells, but failed to induce leukemia in vivo. We provide evidence that VENTX suppresses expression of erythroid master regulators, expands primitive erythroid cells and contributes to leukemogenesis in transplanted mice
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