title: Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair.
abstract: Acute myelogenous leukemias (AMLs) are genetically heterogeneous and characterized by chromosomal rearrangements that produce fusion proteins with aberrant transcriptional regulatory activities. Expression of AML fusion proteins in transgenic mice increases the risk of myeloid leukemias, suggesting that they induce a preleukemic state. The underlying molecular and biological mechanisms are, however, unknown. To address this issue, we performed a systematic analysis of fusion protein transcriptional targets. We expressed AML1/ETO, PML/RAR, and PLZF/RAR in U937 hemopoietic precursor cells and measured global gene expression using oligonucleotide chips. We identified 1,555 genes regulated concordantly by at least two fusion proteins that were further validated in patient samples and finally classified according to available functional information. Strikingly, we found that AML fusion proteins induce genes involved in the maintenance of the stem cell phenotype and repress DNA repair genes, mainly of the base excision repair pathway. Functional studies confirmed that ectopic expression of fusion proteins constitutively activates pathways leading to increased stem cell renewal (e.g., the Jagged1/Notch pathway) and provokes accumulation of DNA damage. We propose that expansion of the stem cell compartment and induction of a mutator phenotype are relevant features underlying the leukemic potential of AML-associated fusion proteins.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. alcalay@ifom-firc.it
authors.forename: Myriam
authors.initials: M
authors.lastname: Alcalay
authors.forename: Natalia
authors.initials: N
authors.lastname: Meani
authors.forename: Vania
authors.initials: V
authors.lastname: Gelmetti
authors.forename: Anna
authors.initials: A
authors.lastname: Fantozzi
authors.forename: Marta
authors.initials: M
authors.lastname: Fagioli
authors.forename: Annette
authors.initials: A
authors.lastname: Orleth
authors.forename: Daniela
authors.initials: D
authors.lastname: Riganelli
authors.forename: Carla
authors.initials: C
authors.lastname: Sebastiani
authors.forename: Enrico
authors.initials: E
authors.lastname: Cappelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Casciari
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sciurpi
authors.forename: Angela Rosa
authors.initials: AR
authors.lastname: Mariano
authors.forename: Simone Paolo
authors.initials: SP
authors.lastname: Minardi
authors.forename: Lucilla
authors.initials: L
authors.lastname: Luzi
authors.forename: Heiko
authors.initials: H
authors.lastname: Muller
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.forename: Guido
authors.initials: G
authors.lastname: Frosina
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit; D004260:DNA Repair; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009154:Mutation; D009363:Neoplasm Proteins / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010641:Phenotype; D011506:Proteins / Q000502:physiology; D000075142:RUNX1 Translocation Partner 1 Protein; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology; D020298:U937 Cells
chemical_list: C107844:AML1-ETO fusion protein, human; D002135:Calcium-Binding Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; D011506:Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin