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A new ETV6-RUNX1 in vivo model produces a phenocopy of the human Pb-ALL
|Autor:||Rodríguez-Hernández, Guillermo; Hauer, Julia; Martín-Lorenzo, Alberto; García-Ramírez, Idoia; González-Herrero, Inés; Ruiz-Roca, Lucía; García Suquía, Marta; Blanco, Óscar; García-Criado, Francisco Javier; Cobaleda, César; Rivas, Javier de las; Vicente-Dueñas, Carolina; Sánchez García, Isidro; Borkhardt, Arndt|
|Fecha de publicación:||2015|
|Citación:||57th ASH Annual Meeting and Exposition (2015)|
|Resumen:||[Introduction]: The ETV6-RUNX1 fusion gene, the most common subtype of childhood pB-ALL, is acquired in utero, producing a persistent and hidden preleukemic clone. However, the underlying mechanism explaining how the preleukemic clone evolves to pB-ALL remains to be identified. The lack of genetically engineered human-like ETV6-RUNX1pB-ALL models has hampered our understanding of the pathogenesis of this disease. [Methods]: We have used a novel experimental approach to generate a murine strain that mimics the human ETV6-RUNX1 pB-ALL. We expressed ETV6-RUNX1 specifically in hematopoietic stem cells (HSC) of C57BL/6 x CBA mice by placing ETV6-RUNX1 under the control of the Sca1 promoter. Two founder mice were obtained for the Sca1-ETV6-RUNX1 transgene, which had normal gestation, were viable and developed normally. Sca1-ETV6-RUNX1 transgenic mice were characterized with respect to clinical, immunephenotypic and genetic characteristics. For the detection of shared secondary genomic alterations we analyzed three murine Sca1-ETV6-RUNX1 and 11 ETV6-RUNX1positive human pB-ALL and corresponding germline by whole-exome (WES) and whole-genome sequencing using a HiSeq 2500 (Illumina) platform.|
[Results]: In our transgenic murine model Sca1-ETV6-RUNX1 transgene expression was detected in HSCs, while there was no detectable expression in pro B cells or later stages of B-cell development, which mimics human ETV6-RUNX1 preleukemic biology. Sca1-ETV6-RUNX1 mice developed exclusively pB-ALL at a low penetrance (7.5%; 3 out of 40) with a CD19+B220+IgM- cell surface phenotype. Overall survival was not significantly reduced compared to wild-type mice (P value = 0.7901). pB-ALL in Sca1-ETV6-RUNX1 mice manifested with splenomegaly, disruption of splenic architecture, and appearance of blast cells in the peripheral blood (PB). All leukemic cells displayed clonal immature BCR rearrangement. Tumor pro B cells grew independent of IL-7 and were able to propagate the disease when transplanted into sub-lethally irradiated syngeneic recipient mice. Whole-exome sequencing of murine pB-ALL revealed in one mouse a deletion of three amino acids in the B-cell differentiation factor EBF1, which is well known in the context of human ETV6-RUNX1 leukemia. Additionally we found mutations in genes implicated in histone modification, i.e. in KDM5Ccausing a premature translation stop. We compared the genomic alterations detected in the mouse model to published genomic data of pediatric ETV6-RUNX1 pB-ALL and identified multiple copy number variations, which are shared between the murine and human ETV6-RUNX1 pB-ALL. Among them were copy number gains and losses including i.e. the tumorsuppressor locus CDKN2A/B with a well-known role in human and mouse pB-ALL. A high proportion of genes implicated in histone modification was also mutated in published data of human ETV6-RUNX1 positive pB-ALL. We validated this novel finding of recurrent alterations of histone modifying genes in both the murine model and the human disease using an independent human ETV6-RUNX1 cohort of 11 patients. In this cohort were able to reproduce this finding. Similar to the murine model, we also detected a missense mutation in the methyltransferase KDM5C in one patient of our cohort of ETV6-RUNX1positive patients.
[Conclusion]: In summary, we have characterized a new Sca1-ETV6-RUNX1 mouse model and this is, to our knowledge the first model, which represents a phenocopy of the human pB-ALL. Sca1-ETV6-RUNX1 mice develop exclusively pB-ALL at a very low penetrance as it is the case in human ETV6-RUNX1 positive pB-ALL. The acquisition of secondary mutations in pB-ALL with a high proportion in histone modifying genes confers the second hit for the conversion of a preleukemic clone into the clinically overt ETV6-RUNX1 positive pB-ALL disease. These findings are important for encouraging novel interventions that might help to prevent or treat ETV6-RUNX1 positive childhood leukemias.
|Descripción:||Resumen del trabajo presentado al 57th American Society of Hematology (ASH) Annual Meeting and Exposition, celebrado en Orlando (Florida-US) del 5 al 8 de diciembre de 2015.-- et al.|
|Aparece en las colecciones:||(IBMCC) Comunicaciones congresos|
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