title: VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice.
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.
authors.affiliation: Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Gentner
authors.affiliation: Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany.
authors.forename: Naidu M
authors.initials: NM
authors.lastname: Vegi
authors.affiliation: Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany.
authors.forename: Medhanie A
authors.initials: MA
authors.lastname: Mulaw
authors.affiliation: Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany.
authors.forename: Tamoghna
authors.initials: T
authors.lastname: Mandal
authors.affiliation: Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany.
authors.forename: Shiva
authors.initials: S
authors.lastname: Bamezai
authors.affiliation: Department of Internal Medicine I, University Hospital Freiburg, 79106 Freiburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.affiliation: Institute of Immunology, Ulm University, 89081 Ulm, Germany.
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Tasdogan
authors.affiliation: Institute of Pathology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Grunenberg
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: MLL Munich Leukemia Laboratory, 81377 Munich, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Buske
authors.affiliation: Institute of Experimental Cancer Research, CCC and University Hospital of Ulm, 89081 Ulm, Germany.
authors.forename: Vijay P S
authors.initials: VP
authors.lastname: Rawat
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Feuring-Buske
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D041905:Erythroid Cells / Q000378:metabolism*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference
chemical_list: D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; C408346:VENTX protein, human
keywords: AML1-ETO; VENTX; acute erythroleukemia; embryonic transcription factor; homeobox gene