The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia
Summary
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. Copyright © 2021 Rodríguez-Hernández, Casado-García, Isidro-Hernández, Picard, Raboso-Gallego, Alemán-Arteaga, Orfao, Blanco, Riesco, Prieto-Matos, García Criado, García Cenador, Hock, Enver, Sanchez-Garcia and Vicente-Dueñas.
| Authors | Rodríguez-Hernández G, Casado-García A, Isidro-Hernández M, Picard D, Raboso-Gallego J, Alemán-Arteaga S, Orfao A, Blanco O, Riesco S, Prieto-Matos P, García Criado FJ, García Cenador MB, Hock H, Enver T, Sanchez-Garcia I, Vicente-Dueñas C |
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| Journal | Frontiers in cell and developmental biology |
| Publication Date | 2021;9:704591 |
| PubMed | 34336858 |
| PubMed Central | PMC8320889 |
| DOI | 10.3389/fcell.2021.704591 |