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PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias.
Ronchini, C; Brozzi, A; Riva, L; Luzi, L; Gruszka, A M; Melloni, G E M; Scanziani, E; Dharmalingam, G; Mutarelli, M; Belcastro, V; Lavorgna, S; Rossi, V; Spinelli, O; Biondi, A; Rambaldi, A; Lo-Coco, F; di Bernardo, D; Pelicci, P G.
Afiliação
  • Ronchini C; Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
  • Brozzi A; Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
  • Riva L; Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
  • Luzi L; Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
  • Gruszka AM; Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
  • Melloni GEM; Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
  • Scanziani E; Mouse &Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy.
  • Dharmalingam G; Dipartimento di Scienze Veterinarie e Sanità Pubblica, Università degli Studi di Milano, Milan, Italy.
  • Mutarelli M; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
  • Belcastro V; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
  • Lavorgna S; Department of Electrical Engineering and Information Technology, University of Naples 'Federico II', Naples, Italy.
  • Rossi V; Department of Biomedicine and Prevention, University of 'Rome Tor Vergata', Rome, Italy.
  • Spinelli O; Laboratorio di Neuro-Oncoematologia, Fondazione Santa Lucia, Rome, Italy.
  • Biondi A; Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Ospedale San Gerardo, Monza, Italy.
  • Rambaldi A; Hematology and Bone Marrow Transplant Unit of Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
  • Lo-Coco F; Clinica Pediatrica, Università di Milano Bicocca, Ospedale San Gerardo, Monza, Italy.
  • di Bernardo D; Hematology and Bone Marrow Transplant Unit of Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
  • Pelicci PG; Department of Biomedicine and Prevention, University of 'Rome Tor Vergata', Rome, Italy.
Leukemia ; 31(9): 1975-1986, 2017 09.
Article em En | MEDLINE | ID: mdl-28025581
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide / Proteínas de Fusão Oncogênica / Redes Reguladoras de Genes / Mutação Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Leukemia Assunto da revista: HEMATOLOGIA / NEOPLASIAS Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide / Proteínas de Fusão Oncogênica / Redes Reguladoras de Genes / Mutação Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Leukemia Assunto da revista: HEMATOLOGIA / NEOPLASIAS Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Itália
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