The vent-like homeobox gene VENTX promotes human myeloid differentiation and is highly expressed in acute myeloid leukemia.
Recent data indicate that a variety of regulatory molecules active in embryonic development may also play a role in the regulation of early hematopoiesis. Here we report that the human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus xvent2 gene, is a unique regulatory hematopoietic gene that is aberrantly expressed in CD34(+) leukemic stem-cell candidates in human acute myeloid leukemia (AML). Quantitative RT-PCR documented expression of the gene in lineage positive hematopoietic subpopulations, with the highest expression in CD33(+) myeloid cells. Notably, expression levels of VENTX were negligible in normal CD34(+)/CD38(-) or CD34(+) human progenitor cells. In contrast to this, leukemic CD34(+)/CD38(-) cells from AML patients with translocation t(8,21) and normal karyotype displayed aberrantly high expression of VENTX. Gene expression and pathway analysis demonstrated that in normal CD34(+) cells enforced expression of VENTX initiates genes associated with myeloid development and down-regulates genes involved in early lymphoid development. Functional analyses confirmed that aberrant expression of VENTX in normal CD34(+) human progenitor cells perturbs normal hematopoietic development, promoting generation of myeloid cells and impairing generation of lymphoid cells in vitro and in vivo. Stable knockdown of VENTX expression inhibited the proliferation of human AML cell lines. Taken together, these data extend our insights into the function of embryonic mesodermal factors in human postnatal hematopoiesis and indicate a role for VENTX in normal and malignant myelopoiesis.
Rawat
Vijay P S
VP
Institute of Experimental Cancer Research, Comprehensive Cancer Center Ulm and University Hospital Ulm, 89081 Ulm, Germany.
Arseni
Natalia
N
Ahmed
Farid
F
Mulaw
Medhanie A
MA
Thoene
Silvia
S
Heilmeier
Bernhard
B
Sadlon
Tim
T
D'Andrea
Richard J
RJ
Hiddemann
Wolfgang
W
Bohlander
Stefan K
SK
Buske
Christian
C
Feuring-Buske
Michaela
M
D018920:Coculture Techniques; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D038042:Myelopoiesis / Q000235:genetics*
D018398:Homeodomain Proteins; C408346:VENTX protein, human