title: Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms.
abstract: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN.
  
  
  
  Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines.
  
  
  
  On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models.
  
  
  
  Trabectedin could be good candidate for clinical studies in JMML/CMML patients.
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Romano
authors.affiliation: Department of Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.|Department of Internal Medicine, University of Pavia, Pavia, Italy.
authors.forename: Matteo Giovanni
authors.initials: MG
authors.lastname: Della Porta
authors.affiliation: Department of Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Gallì
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Panini
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Simonetta Andrea
authors.initials: SA
authors.lastname: Licandro
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Ezia
authors.initials: E
authors.lastname: Bello
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Craparotta
authors.affiliation: IRCCS Policlinico S. Matteo Foundation, Center for the Study of Myelofibrosis, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.affiliation: IRCCS Policlinico S. Matteo Foundation, Center for the Study of Myelofibrosis, Pavia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bonetti
authors.affiliation: Division of Clinical Oncology, IRCCS Fondazione S. Maugeri, Pavia, Italy.
authors.forename: Richard
authors.initials: R
authors.lastname: Tancredi
authors.affiliation: Department of Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mannarino
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Marchini
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Porcu
authors.affiliation: Oncology Unit, PharmaMar SAU Colmenar Viejo, Madrid, Spain.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
authors.affiliation: Medical Oncology Unit, Hospital Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambelli
authors.affiliation: Department of Pediatric Hematology-Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Zecca
authors.affiliation: Department of Pediatric Hematology-Oncology, IRCCS, Bambino Gesù Children's Hospital, Roma, Italy.|Department of Pediatric Science, University of Pavia, Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.|Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Clinica Pediatrica, Università di Milano, Ospedale San Gerardo, Monza, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, Hospital Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: IRCCS Clinical and Research Institute Humanitas, Rozzano, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Allavena
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.affiliation: Department of Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004149:Dioxoles / Q000627:therapeutic use*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D054429:Leukemia, Myelomonocytic, Juvenile / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use*; D000077606:Trabectedin; D014410:Tumor Stem Cell Assay
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin