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Animal models for childhood leukaemia Isidro Sánchez-García ( [email protected] ). 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 ([email protected])

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.

  • 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


Childhood B-ALL development: current working paradigm in the pediatric age group), but its etiology is largely unknown.


Human-based approaches to the study of the etiology of ALL in the pediatric age group), but its etiology is largely unknown.

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.


Mouse-based approaches to the study of the etiology of ALL in the pediatric age group), but its etiology is largely unknown.

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


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


What is the best approach to model mice?

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).


Multiple Myeloma mice?

(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?


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).


Our main ongoing activities in the field of childhood ALL chromosomal translocations

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)


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.


B-ALL target human chromosomal translocations

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


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)


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]


Human childhood B-ALL in mice cells

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.


Different risk factor cells

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


Conclusions cells

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.


Lung & Breast cells

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



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