title: MLL-AF9 oncogene expression affects cell growth but not terminal differentiation and is downregulated during monocyte-macrophage maturation in AML-M5 THP-1 cells.
abstract: The MLL-AF9 oncogene - one of the most frequent MLL/HRX/ALL-1 rearrangements found in infantile and therapy-related leukaemias - originates from t(9;11)(p22;q23) and is mainly associated with monocytic acute myeloid leukaemia (AML-M5; FAB-classification). Here, we investigated the MLL-AF9 function by means of an antisense phosphorothioate-oligodeoxyribonucleotide (MLL-AF9-PS-ODNas) using the THP-1 AML-M5 cell line carrying t(9;11). Having confirmed that MLL-AF9-PS-ODNas induces strong inhibition of THP-1 cell growth, but only a moderate increase in apoptosis, we found that MLL-AF9-PS-ODNas did not induce morpho-functional terminal differentiation or restore M-CSF-, G-CSF- or GM-CSF-induced differentiation. Moreover, THP-1 cells showed the same phenotype with/without MLL-AF9-PS-ODNas. In THP-1 cells differentiated to mature macrophage-like cells by PMA/TPA or ATRA, MLL-AF9 expression was downregulated. Thus, in the monocytic lineage, MLL-AF9 may be expressed only in early phases and can induce deregulated amplification in both nonmalignant and malignant cells, maintaining the monocytic phenotype without blocking final maturation. Our findings suggest that: (1) as well as directly promoting cell growth, MLL-AF9 may also indirectly determine phenotype; (2) other leukaemogenic mutations associated with MLL-AF9-related leukaemias should be searched for mainly in processes of resistance to apoptosis (where MLL-AF9 may play only a limited role) and differentiation blockage (where MLL-AF9 may play no role).
authors.affiliation: Department of Paediatrics, University of Bologna, Policlinico S. Orsola Malpighi, 40138 Bologna, Italy. pession@med.unibo.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Pession
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Martino
authors.forename: Roberto
authors.initials: R
authors.lastname: Tonelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Beltramini
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.forename: Giulia
authors.initials: G
authors.lastname: Biserni
authors.forename: Monica
authors.initials: M
authors.lastname: Franzoni
authors.forename: Francesea
authors.initials: F
authors.lastname: Freccero
authors.forename: Luca
authors.initials: L
authors.lastname: Montemurro
authors.forename: Laura
authors.initials: L
authors.lastname: Pattacini
authors.forename: Guido
authors.initials: G
authors.lastname: Paolucci
mesh_terms: D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D009000:Monocytes / Q000502:physiology*; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology; D009857:Oncogenes / Q000502:physiology*
chemical_list: C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein