title: Cytoskeletal regulatory gene expression and migratory properties of B-cell progenitors are affected by the ETV6-RUNX1 rearrangement.
abstract: Although the ETV6-RUNX1 fusion is a frequent initiating event in childhood leukemia, its role in leukemogenesis is only partly understood. The main impact of the fusion itself is to generate and sustain a clone of clinically silent preleukemic B-cell progenitors (BCP). Additional oncogenic hits, occurring even several years later, are required for overt disease. The understanding of the features and interactions of ETV6-RUNX1-positive cells during this "latency" period may explain how these silent cells can persist and whether they could be prone to additional genetic changes. In this study, two in vitro murine models were used to investigate whether ETV6-RUNX1 alters the cellular adhesion and migration properties of BCP. ETV6-RUNX1-expressing cells showed a significant defect in the chemotactic response to CXCL12, caused by a block in CXCR4 signaling, as demonstrated by inhibition of CXCL12-associated calcium flux and lack of ERK phosphorylation. Moreover, the induction of ETV6-RUNX1 caused changes in the expression of cell-surface adhesion molecules. The expression of genes regulating the cytoskeleton was also affected, resulting in a block of CDC42 signaling. The abnormalities described here could alter the interaction of ETV6-RUNX1 preleukemic BCP with the microenvironment and contribute to the pathogenesis of the disease.
  
  
  CONCLUSIONS
  Alterations in the expression of cytoskeletal regulatory genes and migration properties of BCP represent early events in the evolution of the disease, from the preleukemic phase to the clinical onset, and suggest new strategies for effective eradication of leukemia.
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Chiara
authors: C
authors: Palmi
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Grazia
authors: G
authors: Fazio
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Angela M
authors: AM
authors: Savino
authors: Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors: Julia
authors: J
authors: Procter
authors: Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors: Louise
authors: L
authors: Howell
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Valeria
authors: V
authors: Cazzaniga
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Margherita
authors: M
authors: Vieri
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Giulia
authors: G
authors: Longinotti
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Ilaria
authors: I
authors: Brunati
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Valentina
authors: V
authors: Andrè
authors: Microscopy and Image Analysis Consortium, Università di Milano-Bicocca, Monza, Italy.
authors: Pamela
authors: P
authors: Della Mina
authors: Microscopy and Image Analysis Consortium, Università di Milano-Bicocca, Monza, Italy.
authors: Antonello
authors: A
authors: Villa
authors: Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors: Mel
authors: M
authors: Greaves
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy. abiondi.unimib@gmail.com.
authors: Andrea
authors: A
authors: Biondi
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Giovanna
authors: G
authors: D'Amico
authors: Centre for Evolution and Cancer, Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors: Anthony
authors: A
authors: Ford
authors: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Monza, Italy.
authors: Giovanni
authors: G
authors: Cazzaniga
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D008954:Models, Biological; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D054377:Chemokine CXCL12; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D019718:Receptors, CXCR4; D020764:cdc42 GTP-Binding Protein; C514936:CXCR4 protein, mouse; C581598:Cdc42 protein, mouse; C515256:Cxcl12 protein, mouse; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein