title: The target cell of transformation is distinct from the leukemia stem cell in murine CALM/AF10 leukemia models.
abstract: The CALM/AF10 fusion gene is found in various hematological malignancies including acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia and malignant lymphoma. We have previously identified the leukemia stem cell (LSC) in a CALM/AF10-driven murine bone marrow transplant AML model as B220+ lymphoid cells with B-cell characteristics. To identify the target cell for leukemic transformation or 'cell of origin of leukemia' (COL) in non-disturbed steady-state hematopoiesis, we inserted the CALM/AF10 fusion gene preceded by a loxP-flanked transcriptional stop cassette into the Rosa26 locus. Vav-Cre-induced panhematopoietic expression of the CALM/AF10 fusion gene led to acute leukemia with a median latency of 12 months. Mice expressing CALM/AF10 in the B-lymphoid compartment using Mb1-Cre or CD19-Cre inducer lines did not develop leukemia. Leukemias had a predominantly myeloid phenotype but showed coexpression of the B-cell marker B220, and had clonal B-cell receptor rearrangements. Using whole-exome sequencing, we identified an average of two to three additional mutations per leukemia, including activating mutations in known oncogenes such as FLT3 and PTPN11. Our results show that the COL for CALM/AF10 leukemia is a stem or early progenitor cell and not a cell of B-cell lineage with a phenotype similar to that of the LSC in CALM/AF10+ leukemia.
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Small Animal Medicine, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: A
authors.initials: A
authors.lastname: Krause
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Vosberg
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Herold
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Ksienzyk
authors.affiliation: Institute for Pathology, University Hospital and Faculty of Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Tizazu
authors.affiliation: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
authors.forename: M
authors.initials: M
authors.lastname: Chopra
authors.affiliation: Laboratory for Functional Genome Analysis, Gene Center, Ludwig Maximilians-University, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Graf
authors.affiliation: Laboratory for Functional Genome Analysis, Gene Center, Ludwig Maximilians-University, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Laboratory for Functional Genome Analysis, Gene Center, Ludwig Maximilians-University, Munich, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Blum
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: P A
authors.initials: PA
authors.lastname: Greif
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Vetter
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Metzeler
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rothenberg-Thurley
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Ludwig Maximilians-University, Munich, Germany.
authors.forename: M R
authors.initials: MR
authors.lastname: Schneider
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Ludwig Maximilians-University, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dahlhoff
authors.affiliation: Department of Medicine III, University Hospital Grosshadern, Ludwig Maximilians-University, Munich, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Zimber-Strobl
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Ludwig Maximilians-University, Munich, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
authors.forename: S K
authors.initials: SK
authors.lastname: Bohlander
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D059472:Exome / Q000235:genetics; D005818:Genetic Engineering; D007942:Leukemia, Experimental / Q000473:pathology*; D051379:Mice; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C114359:AF10-CALM fusion protein, human; D015514:Oncogene Proteins, Fusion