title: HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias.
abstract: The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2.
authors.affiliation: Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK.
authors.forename: F J
authors.initials: FJ
authors.lastname: Calero-Nieto
authors.forename: A
authors.initials: A
authors.lastname: Joshi
authors.forename: N
authors.initials: N
authors.lastname: Bonadies
authors.forename: S
authors.initials: S
authors.lastname: Kinston
authors.forename: W-I
authors.initials: WI
authors.lastname: Chan
authors.forename: E
authors.initials: E
authors.lastname: Gudgin
authors.forename: C
authors.initials: C
authors.lastname: Pridans
authors.forename: J-R
authors.initials: JR
authors.lastname: Landry
authors.forename: J
authors.initials: J
authors.lastname: Kikuchi
authors.forename: B J
authors.initials: BJ
authors.lastname: Huntly
authors.forename: B
authors.initials: B
authors.lastname: Gottgens
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics; D017124:Conserved Sequence; D024721:E-Box Elements; D005121:Extremities / Q000196:embryology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055785:Gene Knockdown Techniques; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007438:Introns / Q000235:genetics; D060588:LIM Domain Proteins / Q000172:deficiency / Q000235:genetics*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000196:embryology* / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins