A novel molecular mechanism involved in cancer development revealed by targeting MafB to hematopoietic progenitors

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1 A novel molecular mechanism involved in cancer development revealed by targeting MafB to hematopoietic progenitors Carolina Vicente Dueñas Instituto de Biología Molecular y Celular del Cáncer (IBMCC) (CSIC-Universidad de Salamanca) Salamanca, SPAIN 14 th INTERNATIONAL CONGRESS ASEICA Madrid 23 rd 25 th September- 2013

de Biología Molecular y Celular del Cáncer (IBMCC) (CSIC-Universidad de

2 INTRODUCTION Stem-Cell driven cancer in mice A B ONCOGENE TRANSCRIPTION FACTORS?????????? NORMAL DEVELOPMENT CANCER

3 Targeting oncogenic alterations to the stem cell compartment OBJECTIVE

4 OBJECTIVE How to restrict oncogene expression to the stem cells? Contribution of CSC to cancer biology? Sca1 The key feature of these Sca1 mice is that they express an oncogene under the control of a promoter that is expressed in a population of stem/progenitor cells, but is switched off after lineage commitment.

Sca1 The key feature of these Sca1 mice is that they express an oncogene under

5 OBJECTIVE MULTIPLE MYELOMA MULTIPLE MYELOMA. Plasma cell neoplasia Symptomatic myeloma: - Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma) - A monoclonal protein (paraprotein) in either serum or urine (except in cases of true non-secretory myeloma) - Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, ROTI, commonly referred to by the acronym "CRAB"): HyperCalcemia (corrected calcium >2.75 mmol/l) Renal insufficiency attributable to myeloma Anemia (hemoglobin <10 g/dl) Bone lesions (lytic lesions or osteoporosis with compression fractures) TABLE: The location and oncogenes involved in multiple myeloma Locus Oncogene Incidence 11q13 CCND1 15%-20% 6p21 CCND3 5% 4p16.3 FGFR3 and MMSET 12% 16q23 c-maf 5%-10% 20q11 MAFB 5% 8q24 MYC <10% 6q25 MUM1/IRF4 5% 1q21-34 BCL9, IL6R, MCL1 Frequent HSC CLP pro-b pre-b B cell GENETIC ALTERATION Plasma cell accumulation (MULTIPLE MYELOMA)

either serum or urine (except in cases of true non-secretory myeloma) - Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, ROTI, commonly

6 RESULTS Generation of Sca1-MafB mice ORGAN MALFUNCTION SPLEEN Sca1-MafB Control KIDNEY Sca1-MafB Control Vicente-Dueñas et al. The EMBO Journal (2012)

7 RESULTS Tumor plasma cell infiltrates Vicente-Dueñas et al. The EMBO Journal (2012)

8 RESULTS Abnormal immunoglobulin production by Sca1-MafB mice OLIGOCLONAL IgG INCREASE AMYLOID DEPOSITES IgG Vicente-Dueñas et al. The EMBO Journal (2012)

9 RESULTS Bone lesions in Sca1-MafB mice CONTROL 200X CONTROL CONTROL 100X Sca1-MAF-B 200X Sca1-MAF-B Sca1-MAF-B 100X CONTROL 400X Sca1-MAF-B 400X Sca1-MAF-B 400X HUMAN BONE LESIONS Vicente-Dueñas et al. The EMBO Journal (2012)

Sca1-MAF-B 100X CONTROL 400X Sca1-MAF-B 400X Sca1-MAF-B

10 RESULTS Sca1-MafB stem cells are different from control stem cells GENE EXPRESSION PROFILE GENOME-SCALE DNA METHYLATION ANALYSIS Sca1-MafB HS/P-Cs cells Sca1-MafB B cells WT B cells Sca1-MafB HS/P cells WT HS/P cells WT Myeloid cells CONSERVED METHYLATION CHANGES a) Sca1-MafB B cells b) Sca1-MafB HS/P cells c) WT B cells Vicente-Dueñas et al. The EMBO Journal (2012)

Sca1-MafB HS/P cells WT HS/P cells WT Myeloid cells CONSERVED METHYLATION CHANGES a)

11 REMARKS REMARKS 1- Sca1-MafB mice phenotype recapitulates the features of human Multiple Myeloma. (Marrow Plasmacytosis, Plasmacytoma on Biopsy, M component: serum increase of oligoclonal IgG. Multiorgan plasma cell-related amyloid accumulation, Lytic bone lesions) 2- Restricting oncogene expression to the stem cell compartment is enough to drive specific tumour development. So it is possible to reprogram HSC into tumor cells and this reprograming is mediated by DNA methylation. Vicente-Dueñas et al. The EMBO Journal (2012)

Multiorgan plasma cell-related amyloid accumulation, Lytic bone lesions) 2- Restricting oncogene expression to the stem cell

12 ACKNOWLEDGEMENT Experimental Therapeutics and Translational Oncology Program Cancer Research Center (IBMCC, Salamanca-Spain) Isabel Romero Camarero Inés González-Herrero Esther Alonso Escudero Lucía Ruiz Roca Idoia García Ramírez Alberto Martín Lorenzo Isidro Sánchez-García Clinical Hospital of Salamanca (Spain) - Juan Jesús Cruz (Oncology Department) - Norma C. Gutierrez (Hematology Department) - Teresa Flores (Pathology Department) - Oscar Blanco (Pathology Department) University of Salamanca (Spain) - Rafael Jiménez (Phisiology Department) - Fco. Javier García Criado (Surgery Department) Centro de Biología Molecular Severo Ocho- CBMSO (Madrid) César Cobaleda CIMA José Ángel Martínez-Climent Cancer Research Center (IBMCC, Salamanca-Spain) Jesús Pérez-Losada Pedro A. Lazo Alberto Orfao Spanish National Cancer Centre (CNIO), Madrid (Spain) Mariano Barbacid M.A Piris/ M. Sánchez-Beato Centro Nacional de Biotecnología-CNB (Madrid) Belén Pintado Instituto de Biología Funcional y Genómica (IBFG, Salamanca-Spain) Dionisio Martín-Zanca

Gutierrez (Hematology Department) - Teresa Flores (Pathology Department) - Oscar Blanco (Pathology Department) University of Salamanca (Spain) - Rafael Jiménez (Phisiology Department) - Fco.

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