title: Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia.
abstract: The t(4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34+cells, thereby generating a model of t(4;11) pro-B acute lymphoblastic leukemia (ALL) that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic target binding of the fusion proteins leading to specific gene expression patterns. MLL-Af4 cells can assume a myeloid state under environmental pressure but retain lymphoid-lineage potential. Such incongruity was also observed in t(4;11) patients in whom leukemia evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis.
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Roger T
authors.initials: RT
authors.lastname: Luo
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Anetta
authors.initials: A
authors.lastname: Ptasinska
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Kerry
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Salam A
authors.initials: SA
authors.lastname: Assi
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Kaberlein
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Rayes
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Althoff
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: John
authors.initials: J
authors.lastname: Anastasi
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Maureen M
authors.initials: MM
authors.lastname: O'Brien
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Amom Ruhikanta
authors.initials: AR
authors.lastname: Meetei
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Milne
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: james.mulloy@cchmc.org.
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. Electronic address: mthirman@medicine.bsd.uchicago.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thirman
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D018952:Antigens, CD34; C497422:KMT2A protein, human; C113855:MLL-AF4 fusion protein, human; C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase
keywords: MLL-AF4; acquired resistance to targeted therapy; acute lymphoblastic leukemia; chimeric fusion proteins; mouse models of cancer; species specificity of oncogenes