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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 machinery in pediatric Acute Lymphoblastic Leukemia

AcuteLymphoblasticLeukemia

Most common pediatric malignancy

Disorder of the lymphoblasts

Accumulation of blast cells in BM and PB

Normal

ALL


Introduction machinery in pediatric Acute Lymphoblastic Leukemia

Survival 10%  80%

Risk groups characterization

Well-established treatment protocols directed to risk groups


Introduction
Introduction machinery in pediatric Acute Lymphoblastic Leukemia

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 machinery in pediatric Acute Lymphoblastic Leukemia

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 machinery in pediatric Acute Lymphoblastic Leukemia

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 machinery in pediatric Acute Lymphoblastic Leukemia

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)


Introduction machinery in pediatric Acute Lymphoblastic Leukemia

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


Introduction machinery in pediatric Acute Lymphoblastic Leukemia

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


Introduction machinery in pediatric Acute Lymphoblastic Leukemia

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


Introduction machinery in pediatric Acute Lymphoblastic Leukemia

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


Introduction machinery in pediatric Acute Lymphoblastic Leukemia

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


Micrornas

Introduction machinery in pediatric Acute Lymphoblastic Leukemia

MicroRNAs

1-BINDING


Micrornas1

Introduction machinery in pediatric Acute Lymphoblastic Leukemia

MicroRNAs

1-BINDING

2-LEVEL


Micrornas2

Introduction machinery in pediatric Acute Lymphoblastic Leukemia

MicroRNAs

1-BINDING

2-LEVEL

Adapted from Ryan et al, 2010


Micrornas3

Introduction machinery in pediatric Acute Lymphoblastic Leukemia

MicroRNAs

1-BINDING

2-LEVEL

Adapted from Ryan et al, 2010


Aim machinery in pediatric Acute Lymphoblastic Leukemia

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


Material and machinery in pediatric Acute Lymphoblastic Leukemia 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


Results machinery in pediatric Acute Lymphoblastic Leukemia and Discussion

21 Genes 74 SNPs


Results machinery in pediatric Acute Lymphoblastic Leukemia and Discussion


Results machinery in pediatric Acute Lymphoblastic Leukemia and Discussion


Results machinery in pediatric Acute Lymphoblastic Leukemia and Discussion

Rotunno et al, 2010


Results machinery in pediatric Acute Lymphoblastic Leukemia and Discussion

Rotunno et al, 2010


Results machinery in pediatric Acute Lymphoblastic Leukemia and Discussion

Rotunno et al, 2010


Results machinery in pediatric Acute Lymphoblastic Leukemia and Discussion

42 pre-miRNAs 44 SNPs


Results machinery in pediatric Acute Lymphoblastic Leukemia and Discussion

42 pre-miRNAs 44 SNPs

Targets

ABCC1, ABCC2, ABCC4


Conclusi n

Conclusion machinery in pediatric Acute Lymphoblastic Leukemia

Conclusión

miRNA-related SNPs could be useful toxicity markers


Acknowledgements machinery in pediatric Acute Lymphoblastic Leukemia

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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