The transcription factor c-Myb is an oncoprotein promoting cell proliferation and survival when aberrantly activated/expressed, thus contributing to malignant transformation. Overexpression of c-Myb has been found in leukemias, breast, colon and adenoid cystic carcinoma. Recent studies revealed its expression also in osteosarcoma cell lines and suggested its functional importance during bone development. However, the relevance of c-Myb in control of osteosarcoma progression remains unknown. A retrospective clinical study was carried out to assess a relationship between c-Myb expression in archival osteosarcoma tissues and prognosis in a cohort of high-grade osteosarcoma patients. In addition, MYB was depleted in metastatic osteosarcoma cell lines SAOS-2 LM5 and 143B and their growth, chemosensitivity, migration and metastatic activity were determined. Immunohistochemical analysis revealed that high c-Myb expression was significantly associated with poor overall survival in the cohort and metastatic progression in young patients. Increased level of c-Myb was detected in metastatic osteosarcoma cell lines and its depletion suppressed their growth, colony-forming capacity, migration and chemoresistance in vitro in a cell line-dependent manner. MYB knock-out resulted in reduced metastatic activity of both SAOS-2 LM5 and 143B cell lines in immunodeficient mice. Transcriptomic analysis revealed the c-Myb-driven functional programs enriched for genes involved in the regulation of cell growth, stress response, cell adhesion and cell differentiation/morphogenesis. Wnt signaling pathway was identified as c-Myb target in osteosarcoma cells. Taken together, we identified c-Myb as a negative prognostic factor in osteosarcoma and showed its involvement in the regulation of osteosarcoma cell growth, chemosensitivity, migration and metastatic activity.

1st Department of Pathological Anatomy School of Medicine Masaryk University Brno and St Anne's University Hospital Brno Czech Republic

CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences v v i Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University Kamenice 5 625 00 Brno Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Masaryk University Brno Czech Republic

Department of Pathology University Hospital Brno Brno Czech Republic

Department of Pediatric Oncology University Hospital Brno and School of Medicine Masaryk University Brno Czech Republic

Institute of Physiology University of Zurich Zurich Switzerland

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Masaryk Memorial Cancer Institute Brno Czech Republic

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$a Transcription factor c-Myb: novel prognostic factor in osteosarcoma / $c K. Říhová, M. Dúcka, IS. Zambo, L. Vymětalová, M. Šrámek, F. Trčka, J. Verner, S. Drápela, R. Fedr, T. Suchánková, B. Pavlatovská, E. Ondroušková, I. Kubelková, D. Zapletalová, Š. Tuček, P. Múdry, DA. Krákorová, L. Knopfová, J. Šmarda, K. Souček, L. Borsig, P. Beneš

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$a The transcription factor c-Myb is an oncoprotein promoting cell proliferation and survival when aberrantly activated/expressed, thus contributing to malignant transformation. Overexpression of c-Myb has been found in leukemias, breast, colon and adenoid cystic carcinoma. Recent studies revealed its expression also in osteosarcoma cell lines and suggested its functional importance during bone development. However, the relevance of c-Myb in control of osteosarcoma progression remains unknown. A retrospective clinical study was carried out to assess a relationship between c-Myb expression in archival osteosarcoma tissues and prognosis in a cohort of high-grade osteosarcoma patients. In addition, MYB was depleted in metastatic osteosarcoma cell lines SAOS-2 LM5 and 143B and their growth, chemosensitivity, migration and metastatic activity were determined. Immunohistochemical analysis revealed that high c-Myb expression was significantly associated with poor overall survival in the cohort and metastatic progression in young patients. Increased level of c-Myb was detected in metastatic osteosarcoma cell lines and its depletion suppressed their growth, colony-forming capacity, migration and chemoresistance in vitro in a cell line-dependent manner. MYB knock-out resulted in reduced metastatic activity of both SAOS-2 LM5 and 143B cell lines in immunodeficient mice. Transcriptomic analysis revealed the c-Myb-driven functional programs enriched for genes involved in the regulation of cell growth, stress response, cell adhesion and cell differentiation/morphogenesis. Wnt signaling pathway was identified as c-Myb target in osteosarcoma cells. Taken together, we identified c-Myb as a negative prognostic factor in osteosarcoma and showed its involvement in the regulation of osteosarcoma cell growth, chemosensitivity, migration and metastatic activity.

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