title: Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model.
abstract: HOX genes have emerged as critical effectors of leukemogenesis, but the mechanisms that regulate their expression in leukemia are not well understood. Recent data suggest that the caudal homeobox transcription factors CDX1, CDX2, and CDX4, developmental regulators of HOX gene expression, may contribute to HOX gene dysregulation in leukemia. We report here that CDX4 is expressed normally in early hematopoietic progenitors and is expressed aberrantly in approximately 25% of acute myeloid leukemia (AML) patient samples. Cdx4 regulates Hox gene expression in the adult murine hematopoietic system and dysregulates Hox genes that are implicated in leukemogenesis. Furthermore, bone marrow progenitors that are retrovirally engineered to express Cdx4 serially replate in methylcellulose cultures, grow in liquid culture, and generate a partially penetrant, long-latency AML in bone marrow transplant recipients. Coexpression of the Hox cofactor Meis1a accelerates the Cdx4 AML phenotype and renders it fully penetrant. Structure-function analysis demonstrates that leukemic transformation requires intact Cdx4 transactivation and DNA-binding domains but not the putative Pbx cofactor interaction motif. Together, these data indicate that Cdx4 regulates Hox gene expression in adult hematopoiesis and may serve as an upstream regulator of Hox gene expression in the induction of acute leukemia. Inasmuch as many human leukemias show dysregulated expression of a spectrum of HOX family members, these collective findings also suggest a central role for CDX4 expression in the genesis of acute leukemia.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Dimple
authors.initials: D
authors.lastname: Bansal
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McDowell
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Davidson
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Brian J P
authors.initials: BJ
authors.lastname: Huntly
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C084563:Cdx4 protein, mouse; D004273:DNA, Neoplasm; D018398:Homeodomain Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins