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Animal models for childhood leukaemia Isidro Sánchez-García ( isg@usal.es )

Animal models for childhood leukaemia Isidro Sánchez-García ( isg@usal.es ). 5th I4C meeting, 12-13Nov 2012, Lyon, France. - ALL is the commenest childhood malignancy (80% of leukemia in the pediatric age group), but its etiology is largely unknown.

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Animal models for childhood leukaemia Isidro Sánchez-García ( isg@usal.es )

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  1. Animal models for childhood leukaemia Isidro Sánchez-García (isg@usal.es) 5th I4C meeting, 12-13Nov 2012, Lyon, France

  2. - ALL is the commenest childhood malignancy (80% of leukemia in the pediatric age group), but its etiology is largely unknown. • B-cell precursor (BCP)-ALL is the main form of the disease, accounting for approximately 85% of all pediatric ALL. • Chimeric fusion genes are common in childhood ALL but insufficient for leukemia to develop. Two main fusion genes in childhood ALL: BCR-ABL1 and TEL-AML1

  3. Childhood B-ALL development: current working paradigm

  4. Human-based approaches to the study of the etiology of ALL Limitations on B-ALL research in humans: GWAS studies allow identification of the additive variance as a proportion of the phenotypic variance (human studies). -Current GWAS do not provide identification of non-additive genetic variance (gene-gene interactions or dominant effects)… -Current GWAS do not identify gene-environmental interactions Appropiate mouse models could allow to identify for the complex cascade of developmental steps that occur in childhood leukaemia.

  5. Mouse-based approaches to the study of the etiology of ALL common genetic initiating event genotype-phenotype relationship + Genetic determinants? + Tests for potential environmental factors Mouse model of ALL Mouse models of childhood leukemia would be very useful

  6. Is possible to have primary/spontaneous childhood ALL in mice? Rx, Magnetic Fields, Immunizations, Infections, Chemical, etc as primary events Human childhood leukemia Mice do not develop B-cell leukemia spontaneously Mice do not develop B-cell leukemia common genetic initiating event genotype-phenotype relationship + genetic determinants ? NPPs associated B-ALL have similar characteristics initiating event found in children never happens in the mice

  7. What is the best approach to model childhood ALL induction and development in mice? Human ALL is a disease of the organism within an inmmunocompetent body Patient-derived tumour xenografts as models for oncology BioEssays 29 (12): 1269-1280 (2007) & Bioessays 31(6):600-609 (2009).

  8. Multiple Myeloma (MafB) Lymhoma MALT (Malt1) Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 MafB MafB Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 MafB Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 p190 Malt1 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 p190 Bcl6 Bcl6 Bcl6 Bcl6 HGAL Bcl6 Lmo2 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Bcl6 Lmo2 B cell lymphoma (BCL6) HGAL B cell lymphoma (HGAL) B cell development B-ALL (Tel-Aml1; BCRABLp190) B cell lymphoma (Lmo2) Contribution of childhood ALL to cancer biology?

  9. Childhood ALL mouse models based on a B-cell origin of human chromosomal translocations Approaches used to directly model TEL-AML1-B-ALL disease rely on the use of genetically engineered mouse models to induce the ectopic expression of the oncogene in different stages of B cell development. However, this approach of targeting the TEL-AML1 oncogene to mouse B-cells has failed to recapitulate the human disease (Schindler J Cell Stem Cell 2008; van der Weyden Blood 2011).

  10. Our main ongoing activities in the field of childhood ALL and mouse models 1997 2000 2007 2012 2009 fusion gene associated with B-ALL by knock-in technology (Blood 1997) Availablechildhood ALL mousemodels: TEL-AML1 BCR-ABLp190 a stem cell is the leukaemia-maintaining-cell in human BCR-ABLp190+ B-ALL (Blood2000) Fusion gene is not required to maintain B-ALL phenotype in a conditional mouse model by tet-off technology (Oncogene 2007) first mouse model of fusion gene associated with leukaemia based on the cancer-stem-cell concept (EMBO J.2009) Expression of MALT1, MafB and HGAL in stem cells recapitulates pathogenesis of human diseases (PNAS 2012; EMBO J 2012, and Nature Communications 2012)

  11. Childhood ALL mouse models based on a stem-cell origin of human chromosomal translocations Vicente-Dueñas C, et al Dis Model Mech. 2010;3(3-4):149-55.

  12. B-ALL target Biologicalcriteria Similar histologicalfeatures (human pathologists) Progressthroughthesamestages iii) They cause thesamesystemic effectsonthehost Thesamegeneticpathways in tumor initiation/ progression. Theyrespond in thesamewayto currenttherapeuticapproaches. Molecular Target B-ALL Target Cellular Target Mouse model of childhood B-ALL recapitulating genotype-phenotype correlations

  13. Stem cell driven leukemia in mice predicts human clinical results • 1- First animal model aniticipating human clinical results • Results confirmed in human patients: Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ.Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011 Jan 4;121(1):396-409. Perez-Caro et al. EMBO J. 28(1):8-20 (2009). Vicente-Dueñas et al. Cell Cycle 8:1314-1318 (2009) Sanchez-Garcia I. N Engl J Med. 360(3):297-299 (2009)

  14. Genome-scale DNA methylation maps of stem cells and mature B cells in mice predicts human cancer organization Figure 5 from Carolina Vicente-Dueñas et al. The EMBO Journal online publication 17 August 2012 doi:10.1038/emboj.2012.227 Whether this mechanism is involved in the genesis of human cancers was presently not known, but recent results confirmed similar cellular hierarchy n human MM patients: Boucher K, et al Clin Cancer Res. 2012 Sep 17. [Epub ahead of print]

  15. Human childhood B-ALL in mice oncogene B-A T-A B-A T-A B-A T-A B-A T-A B-A T-A B-A T-A B-A T-A B-A T-A B-A T-A B-A T-A i) Like in humans, these mouse models do not develop a too-rapid leukemic process. ii) The appearance of this fusion gene in a the mouse model does not commit the cell to evolve into a malignant disease, as 50% of the mice do not develop the disease similar, to children who harbour TEL-AML1 but never develop B-ALL (Pui et al., 2004), indicating that secondary cooperative changes in the mouse’s genome seem to be necessary for the disease expression.

  16. Different risk factor exposure susceptibility F1 Backcross ± Study physiological variability Experiment design Susceptible Strain (FvB) Population with high genetic variability primed for B-ALL (inherited susceptibilities) Resistant strain (B6) X potential environmental risk factors/ carcinogen to study gene-enviroment interactions F1 B6 x FVB High leukemia phenotype variability (tumor phenotype and genetics) Study genomic (SNPs) and epigenetic variability before and after to identify risk factors

  17. Conclusions Sporadic B-ALL is a polygenic disease influenced by the effects of multiple low penetrance genes that interact among them and with the environment, determining that some individuals develop B-ALL and others are resistant under the same environmental conditions. To identify those low penetrance modifier genes in the human population is a difficult task due to the genetic heterogeneity and the complex interaction with the environment, so it is necessary to embark expensive and long time consuming large population studies without guarantee of final success. Although these studies have convincingly identified numerous common alleles, there is accumulating evidence that the individual effects of low penetrance modifier genes are so small that genome-wide association studies will not identify the bulk of unexplained heritable risk in the foreseeable future. We think that these new mouse strains with homogenous genome and with quite uniform phenotypes, with environmental conditions highly controlled in the state of the art animal house facilities offer a unique opportunity to tackle this question.

  18. Lung & Breast CNIO Madrid Mariano Barbacid USC-Santiago Compostela Angel Carracedo IBMCC-Salamanca Jesus Perez-Losada Acknowledgements Childhood Leukemia IBMCC (CSIC/USAL) Salamanca Carolina Vicente Dueñas Isabel Romero Camarero Lucía Ruiz-Roca Inés González Herrero Esther Alonso Escudero Marcos Barajas-Diego Alberto Martín Lorenzo Isidro Sánchez-García Lymphoma IMB- Salamanca Dionisio Martín-Zanca U. Miami-USA Izidore Lossos Multyple myeloma CBMSO Madrid César Cobaleda Stanford-USA Ash Alizadeh IBMCC-Salamanca Jesus F San Miguel Imperial-London Cristina Lo Celso Cornell Institute (NY) Ari Melnick Sanger Institute-Cambridge Natalie Conte Allan Bradley IMP Vienna Meinrad Busslinger IBMCC-Salamanca Alberto Orfao Universidad Salamanca Hospital Clínico Univ. Teresa Flores MD Ludeña Juan Jesus Cruz Gonzalo Varela Concha Roman Fco Javier Garcia Criado Rafael Jiménez CIMA- Pamplona Jose A. Martinez-Climent CBMSO Madrid César Cobaleda Transgenic Unit CNB-CBMSO Belén Pintado Verónica Domínguez Ingenio 2010 CDTEAM Fundacion Sandra Ibarra

  19. Thank you for your attention !!!!

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