title: PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias.
abstract: It has been shown that individual acute myeloid leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5-10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional-mutagenesis screen for genes cooperating with one AML initiating mutations (PML-RARA, oncogene of acute promyelocytic leukemia, APL), which allowed identification of hundreds of genetic cooperators. The cooperators are mutated at low frequency in APL or AML patients but are always abnormally expressed in a cohort of 182 APLs and AMLs analyzed. These deregulations appear non-randomly distributed and present in all samples, regardless of their associated genomic mutations. Reverse-engineering approaches showed that these cooperators belong to a single transcriptional gene network, enriched in genes mutated in AMLs, where perturbation of single genes modifies expression of others. Their gene-ontology analysis showed enrichment of genes directly involved in cell proliferation control. Therefore, the pool of PML-RARA cooperating mutations appears large and heterogeneous, but functionally equivalent and deregulated in the majority of APLs and AMLs. Our data suggest that the high heterogeneity of DNA mutations in APLs and AMLs can be reduced to patterns of gene expression deregulation of a single 'mutated' gene network.
authors.affiliation: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ronchini
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Brozzi
authors.affiliation: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Riva
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Luzi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Gruszka
authors.affiliation: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: G E M
authors.initials: GEM
authors.lastname: Melloni
authors.affiliation: Mouse &Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy.|Dipartimento di Scienze Veterinarie e Sanità Pubblica, Università degli Studi di Milano, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Scanziani
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Dharmalingam
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mutarelli
authors.affiliation: Department of Electrical Engineering and Information Technology, University of Naples 'Federico II', Naples, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Belcastro
authors.affiliation: Department of Biomedicine and Prevention, University of 'Rome Tor Vergata', Rome, Italy.|Laboratorio di Neuro-Oncoematologia, Fondazione Santa Lucia, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Lavorgna
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Rossi
authors.affiliation: Hematology and Bone Marrow Transplant Unit of Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Spinelli
authors.affiliation: Clinica Pediatrica, Università di Milano Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Hematology and Bone Marrow Transplant Unit of Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: Department of Biomedicine and Prevention, University of 'Rome Tor Vergata', Rome, Italy.|Laboratorio di Neuro-Oncoematologia, Fondazione Santa Lucia, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Lo-Coco
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: D
authors.initials: D
authors.lastname: di Bernardo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Dipartimento di Scienze della salute, Università degli Studi di Milano, Milan, Italy.
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D030541:Databases, Genetic; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute; D015473:Leukemia, Promyelocytic, Acute; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics*
chemical_list: D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein