title: The leukemogenicity of Hoxa9 depends on alternative splicing.
abstract: Although the transforming potential of Hox genes is known for a long time, it is not precisely understood to which extent splicing is important for the leukemogenicity of this gene family. To test this for Hoxa9, we compared the leukemogenic potential of the wild-type Hoxa9, which undergoes natural splicing, with a full-length Hoxa9 construct, which was engineered to prevent natural splicing (Hoxa9FLim). Inability to undergo splicing significantly reduced in vivo leukemogenicity compared to Hoxa9-wild-typed. Importantly, Hoxa9FLim could compensate for the reduced oncogenicity by collaborating with the natural splice variant Hoxa9T, as co-expression of Hoxa9T and Hoxa9FLim induced acute myeloid leukemia (AML) after a comparable latency time as wild-type Hoxa9. Hoxa9T on its own induced AML after a similar latency as Hoxa9FLim, despite its inability to bind DNA. These data assign splicing a central task in Hox gene mediated leukemogenesis and suggest an important role of homeodomain-less splice variants in hematological neoplasms.
authors.affiliation: 1] Department of Internal Medicine III, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany [2] Clinical Cooperative Group 'Pathogenesis of Acute Myeloid Leukemia', Helmholtz Center Munich for Environmental Health, Munich, Germany.
authors.forename: C R
authors.initials: CR
authors.lastname: Stadler
authors.affiliation: Institute of Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Vegi
authors.affiliation: Institute of Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Mulaw
authors.affiliation: Institute of Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: K E
authors.initials: KE
authors.lastname: Edmaier
authors.affiliation: Institute of Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: V P S
authors.initials: VP
authors.lastname: Rawat
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dolnik
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Oncology and Hematology, Hospital Barmherzige Brüder, Regensburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Heilmeier
authors.affiliation: Institute of Pathology, University of Tübingen, Tübingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Quintanilla-Fend
authors.affiliation: 1] Department of Internal Medicine III, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany [2] Clinical Cooperative Group 'Pathogenesis of Acute Myeloid Leukemia', Helmholtz Center Munich for Environmental Health, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: 1] Department of Internal Medicine III, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany [2] Clinical Cooperative Group 'Pathogenesis of Acute Myeloid Leukemia', Helmholtz Center Munich for Environmental Health, Munich, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Feuring-Buske
authors.affiliation: Institute of Experimental Cancer Research, Comprehensive Cancer Center, University Hospital of Ulm, Ulm, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Buske
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL
chemical_list: D018398:Homeodomain Proteins; C097899:homeobox protein HOXA9