title: Enforced expression of the homeobox gene Mixl1 impairs hematopoietic differentiation and results in acute myeloid leukemia.
abstract: Mixl1, the sole murine homologue of the Xenopus Mix/Bix family of homeobox transcription factors, is essential for the patterning of axial mesendodermal structures during early embryogenesis. Gene targeting and overexpression studies have implicated Mixl1 as a regulator of hematopoiesis arising in differentiating embryonic stem cells. To assess the role of Mixl1 in the regulation of adult hematopoiesis, we overexpressed Mixl1 in murine bone marrow using a retroviral transduction/transplantation model. Enforced expression of Mixl1 profoundly perturbed hematopoietic lineage commitment and differentiation, giving rise to abnormal myeloid progenitors and impairing erythroid and lymphoid differentiation. Moreover, all mice reconstituted with Mixl1-transduced bone marrow developed fatal, transplantable acute myeloid leukemia with a mean latency period of 200 days. These observations establish a link between enforced Mixl1 expression and leukemogenesis in the mouse.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Glaser
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Adam H
authors.initials: AH
authors.lastname: Hart
authors.forename: Ladina
authors.initials: L
authors.lastname: DiRago
authors.forename: Sandra
authors.initials: S
authors.lastname: Mifsud
authors.forename: Angela
authors.initials: A
authors.lastname: D'Amico
authors.forename: Samantha
authors.initials: S
authors.lastname: Dagger
authors.forename: Chiara
authors.initials: C
authors.lastname: Campo
authors.forename: Angela C
authors.initials: AC
authors.lastname: Chan
authors.forename: David J
authors.initials: DJ
authors.lastname: Izon
authors.forename: Lorraine
authors.initials: L
authors.lastname: Robb
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D015996:Survival Rate
chemical_list: D018398:Homeodomain Proteins; C464781:Mixl1 protein, mouse