Data_Sheet_1_The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia.pdf (2.12 MB)
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Data_Sheet_1_The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia.pdf

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posted on 15.07.2021, 14:41 by Guillermo Rodríguez-Hernández, Ana Casado-García, Marta Isidro-Hernández, Daniel Picard, Javier Raboso-Gallego, Silvia Alemán-Arteaga, Alberto Orfao, Oscar Blanco, Susana Riesco, Pablo Prieto-Matos, Francisco Javier García Criado, María Begoña García Cenador, Hanno Hock, Tariq Enver, Isidro Sanchez-Garcia, Carolina Vicente-Dueñas

ETV6-RUNX1 is almost exclusively associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequences of ETV6-RUNX1 expression on cell lineage decisions during B-cell leukemogenesis are completely unknown. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but few carriers develop B-ALL as a result of secondary genetic alterations. The understanding of the mechanisms underlying the first transforming steps could greatly advance the development of non-toxic prophylactic interventions. Using genetic lineage tracing, we examined the capacity of ETV6-RUNX1 to instruct a malignant phenotype in the hematopoietic lineage by cell-specific Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 gene locus. Here we show that, while ETV6-RUNX1 has the propensity to trigger both T- and B-lymphoid malignancies, it is the second hit that determines tumor cell identity. To instigate leukemia, both oncogenic hits must place early in the development of hematopoietic/precursor cells, not in already committed B-cells. Depending on the nature of the second hit, the resulting B-ALLs presented distinct entities that were clearly separable based on their gene expression profiles. Our findings give a novel mechanistic insight into the early steps of ETV6-RUNX1+ B-ALL development and might have major implications for the potential development of ETV6-RUNX1+ B-ALL prevention strategies.