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

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slide1

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

acute lymphoblastic leukemia

Introduction

AcuteLymphoblasticLeukemia

Most common pediatric malignancy

Disorder of the lymphoblasts

Accumulation of blast cells in BM and PB

Normal

ALL

slide3

Introduction

Survival 10%  80%

Risk groups characterization

Well-established treatment protocols directed to risk groups

introduction
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)

introduction1
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)

introduction2
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)

introduction3
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)

slide8

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

slide9

Introduction

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

slide10

Introduction

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

slide11

Introduction

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

slide12

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

micrornas1

Introduction

MicroRNAs

1-BINDING

2-LEVEL

micrornas2

Introduction

MicroRNAs

1-BINDING

2-LEVEL

Adapted from Ryan et al, 2010

micrornas3

Introduction

MicroRNAs

1-BINDING

2-LEVEL

Adapted from Ryan et al, 2010

slide17

Aim

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

slide18

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

slide19

Results and Discussion

21 Genes 74 SNPs

slide22

Results and Discussion

Rotunno et al, 2010

slide23

Results and Discussion

Rotunno et al, 2010

slide24

Results and Discussion

Rotunno et al, 2010

slide25

Results and Discussion

42 pre-miRNAs 44 SNPs

slide26

Results and Discussion

42 pre-miRNAs 44 SNPs

Targets

ABCC1, ABCC2, ABCC4

conclusi n

Conclusion

Conclusión

miRNA-related SNPs could be useful toxicity markers

slide28

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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