AUTHOR=Rodríguez-Hernández Guillermo , Casado-García Ana , Isidro-Hernández Marta , Picard Daniel , Raboso-Gallego Javier , Alemán-Arteaga Silvia , Orfao Alberto , Blanco Oscar , Riesco Susana , Prieto-Matos Pablo , García Criado Francisco Javier , García Cenador María Begoña , Hock Hanno , Enver Tariq , Sanchez-Garcia Isidro , Vicente-Dueñas Carolina TITLE=The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=9 YEAR=2021 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.704591 DOI=10.3389/fcell.2021.704591 ISSN=2296-634X ABSTRACT=

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.