title: The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice.
abstract: The t(10;11)(p13-14;q14-21) translocation, giving rise to the CALM-AF10 fusion gene, is a recurrent chromosomal rearrangement observed in patients with poor prognosis acute myeloid leukemia (AML). Although splicing of the CALM-AF10 fusion transcripts has been described in AML patients, the contribution of different CALM and AF10 domains to in vivo leukemogenesis remains to be defined. We therefore performed detailed structure-function studies of the CALM-AF10 fusion protein. We demonstrate that fusion of the C-terminal 248 amino acids of CALM, which include the clathrin-binding domain, to the octapeptide motif-leucine-zipper (OM-LZ) domain of AF10 generated a fusion protein (termed CALM-AF10 minimal fusion (MF)), with strikingly enhanced transformation capabilities in colony assays, providing an efficient system for the expeditious assessment of CALM-AF10-mediated transformation. Leukemias induced by the CALM-AF10 (MF) mutant recapitulated multiple aspects of full-length CALM-AF10-induced leukemia, including aberrant Hoxa cluster upregulation, a characteristic molecular lesion of CALM-AF10 leukemias. In summary, this study indicates that collaboration of the clathrin-binding and the OM-LZ domains of CALM-AF10 is sufficient to induce AML. These findings further suggest that future approaches to antagonize CALM-AF10-induced transformation should incorporate strategies, which aim at blocking these key domains.
authors.affiliation: Department of Medicine III, Klinikum Grosshadern, Munich, Germany.
authors.forename: A J
authors.initials: AJ
authors.lastname: Deshpande
authors.forename: A
authors.initials: A
authors.lastname: Rouhi
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: C
authors.initials: C
authors.lastname: Stadler
authors.forename: P A
authors.initials: PA
authors.lastname: Greif
authors.forename: N
authors.initials: N
authors.lastname: Arseni
authors.forename: S
authors.initials: S
authors.lastname: Opatz
authors.forename: L
authors.initials: L
authors.lastname: Quintanilla-Fend
authors.forename: K
authors.initials: K
authors.lastname: Holzmann
authors.forename: W
authors.initials: W
authors.lastname: Hiddemann
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.forename: S A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: S K
authors.initials: SK
authors.lastname: Bohlander
authors.forename: C
authors.initials: C
authors.lastname: Buske
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D034041:Monomeric Clathrin Assembly Proteins / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002966:Clathrin; C490477:Mllt10 protein, mouse; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D014157:Transcription Factors