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Acute Lymphoblastic Leukemia

Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric Acute Lymphoblastic Leukemia.

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Acute Lymphoblastic Leukemia

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  1. Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric Acute Lymphoblastic Leukemia Elixabet López-López, Ángela Gutierrez-Camino, Idoia Martín-Guerrero, M Ángeles Piñán, Nagore García de Andoin, Aurora Navajas, Purificación García-Miguel, Javier Ballesteros, África García-Orad

  2. Introduction AcuteLymphoblasticLeukemia Most common pediatric malignancy Disorder of the lymphoblasts Accumulation of blast cells in BM and PB Normal ALL

  3. Introduction Survival 10%  80% Risk groups characterization Well-established treatment protocols directed to risk groups

  4. Introduction LAL/SHOP protocol SR Induction Consolidation Maintenance DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR PDN MTX 6MP TIT (MTX) HR Induction Consolidation Intensification Maintenance DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) epiADR VCR DEXA CFM MTX ASP AraC TIT (MTX) VCR PDN ASP MTX 6MP CFM TIT (MTX) Induction Consolidation Blocks Intensification Graft VHR DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR DNR DEXA CFM MTX ASP AraC TIT (MTX)

  5. Introduction LAL/SHOP protocol SR Induction Consolidation Maintenance DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR PDN MTX 6MP TIT (MTX) HR Induction Consolidation Intensification Maintenance DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) epiADR VCR DEXA CFM MTX ASP AraC TIT (MTX) VCR PDN ASP MTX 6MP CFM TIT (MTX) Induction Consolidation Blocks Intensification Graft VHR DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR DNR DEXA CFM MTX ASP AraC TIT (MTX)

  6. Introduction LAL/SHOP protocol SR Induction Consolidation Maintenance DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR PDN MTX 6MP TIT (MTX) • Toxicity • - Requirestreatmentreduction HR Induction Consolidation Intensification Maintenance DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) epiADR VCR DEXA CFM MTX ASP AraC TIT (MTX) VCR PDN ASP MTX 6MP CFM TIT (MTX) Induction Consolidation Blocks Intensification Graft VHR DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR DNR DEXA CFM MTX ASP AraC TIT (MTX)

  7. Introduction LAL/SHOP protocol SR Induction Consolidation Maintenance DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR PDN MTX 6MP TIT (MTX) • Toxicity • - Requirestreatmentreduction PREDICTIVE MARKERS HR Induction Consolidation Intensification Maintenance DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) epiADR VCR DEXA CFM MTX ASP AraC TIT (MTX) VCR PDN ASP MTX 6MP CFM TIT (MTX) Induction Consolidation Blocks Intensification Graft VHR DNR VCR PDN CFM ASP TIT (MTX) MTX 6MP AraC TIT (MTX) VCR DNR DEXA CFM MTX ASP AraC TIT (MTX)

  8. Introduction SLC19A1 SLCO1B1 LIVER CELL SLCO1A2 MTX MTX SLCO1B3 • 384 SNPs • 151 B-ALL • LAL/SHOP ABCB1 ABCG2 ABCC1 ABCC2 ABCC3 Via bloodstream Via bile SLC22A6 SLC22A8 Elimination ABCC4 KIDNEY CELL Elimination ABCC2 ABCG2

  9. Introduction E. Lopez-Lopez et al. Pharmacogenetics and Genomics 2013

  10. Introduction E. Lopez-Lopez et al. Pharmacogenetics and Genomics 2013

  11. Introduction E. Lopez-Lopez et al. Pharmacogenetics and Genomics 2013

  12. Introduction SLC19A1 SLCO1B1 LIVER CELL SLCO1A2 SLCO1B3 E. Lopez-Lopez et al. Pharmacogenetics and Genomics 2013 ABCB1 ABCG2 ABCC1 ABCC3 Via bloodstream MTX MTX Via bile SLC22A6 SLC22A8 ABCC2 Elimination ABCC4 KIDNEY CELL Elimination ABCC2 ABCG2

  13. Introduction MicroRNAs 1-BINDING

  14. Introduction MicroRNAs 1-BINDING 2-LEVEL

  15. Introduction MicroRNAs 1-BINDING 2-LEVEL Adapted from Ryan et al, 2010

  16. Introduction MicroRNAs 1-BINDING 2-LEVEL Adapted from Ryan et al, 2010

  17. Aim To detect new toxicity markers in pediatric B-ALL patients studying miRNA-related polymorphisms

  18. Material and methods • miRNAs biogenesis and processing genes: • MAF: 5% • Functional SNPs • bibliographic • premiRNAs: • MAF: 1% 118 SNPs 152 children with B-ALL LAL/SHOP Taqman Openarray

  19. Results and Discussion 21 Genes 74 SNPs

  20. Results and Discussion

  21. Results and Discussion

  22. Results and Discussion Rotunno et al, 2010

  23. Results and Discussion Rotunno et al, 2010

  24. Results and Discussion Rotunno et al, 2010

  25. Results and Discussion 42 pre-miRNAs 44 SNPs

  26. Results and Discussion 42 pre-miRNAs 44 SNPs Targets ABCC1, ABCC2, ABCC4

  27. Conclusion Conclusión miRNA-related SNPs could be useful toxicity markers

  28. Acknowledgements A. Navajas MA. Piñán A. García-Orad I. Martín Guerrero A. Gutiérrez-Camino N. Bilbao M. Pombar Z. Askaiturrieta J. Ballesteros B. Santos J. Uriz N. García de Andoin P. García-Miguel

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