title: The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets.
abstract: BACKGROUND
  The malignant B cells in chronic lymphocytic leukemia receive signals from the bone marrow and lymph node microenvironments which regulate their survival and proliferation. Characterization of these signals and the pathways that propagate them to the interior of the cell is important for the identification of novel potential targets for therapeutic intervention.
  
  
  METHODS
  We compared the gene expression profiles of chronic lymphocytic leukemia B cells purified from bone marrow and peripheral blood to identify genes that are induced by the bone marrow microenvironment. Two of the differentially expressed genes were further studied in cell culture experiments and in an animal model to determine whether they could represent appropriate therapeutic targets in chronic lymphocytic leukemia.
  
  
  RESULTS
  Functional classification analysis revealed that the majority of differentially expressed genes belong to gene ontology categories related to cell cycle and mitosis. Significantly up-regulated genes in bone marrow-derived tumor cells included important cell cycle regulators, such as Aurora A and B, survivin and CDK6. Down-regulation of Aurora A and B by RNA interference inhibited proliferation of chronic lymphocytic leukemia-derived cell lines and induced low levels of apoptosis. A similar effect was observed with the Aurora kinase inhibitor VX-680 in primary chronic lymphocytic leukemia cells that were induced to proliferate by CpG-oligonucleotides and interleukin-2. Moreover, VX-680 significantly blocked leukemia growth in a mouse model of chronic lymphocytic leukemia.
  
  
  CONCLUSIONS
  Aurora A and B are up-regulated in proliferating chronic lymphocytic leukemia cells and represent potential therapeutic targets in this disease.
authors.affiliation: Hematology Division and Center for Cell-Based Therapy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Francisco
authors.initials: F
authors.lastname: de Paula Careta
authors.forename: Stefania
authors.initials: S
authors.lastname: Gobessi
authors.forename: Rodrigo Alexandre
authors.initials: RA
authors.lastname: Panepucci
authors.forename: Engin
authors.initials: E
authors.lastname: Bojnik
authors.forename: Fabio
authors.initials: F
authors.lastname: Morato de Oliveira
authors.forename: Daniel
authors.initials: D
authors.lastname: Mazza Matos
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Falcão
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.forename: Marco A
authors.initials: MA
authors.lastname: Zago
authors.forename: Dimitar G
authors.initials: DG
authors.lastname: Efremov
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D051379:Mice; D008938:Mitosis / Q000235:genetics; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D064127:Aurora Kinases; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576918:Aurka protein, mouse