| First Author | Rodríguez-Hernández G | Year | 2021 |
| Journal | Front Cell Dev Biol | Volume | 9 |
| Pages | 704591 | PubMed ID | 34336858 |
| Mgi Jnum | J:308594 | Mgi Id | MGI:6730710 |
| Doi | 10.3389/fcell.2021.704591 | Citation | Rodriguez-Hernandez G, et al. (2021) The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia. Front Cell Dev Biol 9:704591 |
| abstractText | 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. |
