title: Importance of a specific amino acid pairing for murine MLL leukemias driven by MLLT1/3 or AFF1/4.
abstract: Acute leukemias caused by translocations of the MLL gene at chromosome 11 band q23 (11q23) are characterized by a unique gene expression profile. More recently, data from several laboratories indicate that the most commonly encountered MLL fusion proteins, MLLT1, MLLT3, and AFF1 are found within a molecular complex that facilitates the elongation phase of mRNA transcription. Mutational analyses suggest that interaction between the MLLT1/3 proteins and AFF family proteins are required for experimental transformation of hematopoietic progenitor cells (HPCs). Here, we define a specific pairing of two amino acids that creates a salt bridge between MLLT1/3 and AFF proteins that is critically important for MLL-mediated transformation of HPCs. Our findings, coupled with the newly defined structure of MLLT3 in complex with AFF1, should facilitate the development of small molecules that block this amino acid interaction and interfere with the activity of the most common MLL oncoproteins.
authors.affiliation: The Molecular Biology Program, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, United States.
authors.forename: Alyson A
authors.initials: AA
authors.lastname: Lokken
authors.affiliation: Oncology Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Achille
authors.affiliation: Department of Biochemistry, Tulane University School of Medicine, New Orleans, LA 70112, United States.
authors.forename: Ming-Jin
authors.initials: MJ
authors.lastname: Chang
authors.affiliation: Department of Biochemistry, Tulane University School of Medicine, New Orleans, LA 70112, United States.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, United States.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Kuntimaddi
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, United States.
authors.forename: Benjamin I
authors.initials: BI
authors.lastname: Leach
authors.affiliation: The Molecular Biology Program, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, United States.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Malik
authors.affiliation: Department of Biochemistry, Tulane University School of Medicine, New Orleans, LA 70112, United States.
authors.forename: Jacqueline B
authors.initials: JB
authors.lastname: Nesbit
authors.affiliation: Oncology Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, United States.
authors.forename: Shubin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, United States.
authors.forename: John H
authors.initials: JH
authors.lastname: Bushweller
authors.affiliation: Oncology Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, United States; Department of Medicine, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, United States. Electronic address: nzelezn@luc.edu.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Zeleznik-Le
authors.affiliation: Oncology Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, United States; Department of Pediatrics, Loyola University Chicago Health Sciences Division, Maywood, IL 60153, United States. Electronic address: chemenway@lumc.edu.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Hemenway
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics*; D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D035602:Transcriptional Elongation Factors
chemical_list: C503581:Aff4 protein, mouse; D000596:Amino Acids; D004268:DNA-Binding Proteins; C493508:Mllt1 protein, mouse; C489902:Mllt3 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors
keywords: Leukemic transformation; Mutation complementation; Oncoproteins; Protein binding