The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia

• DOI: 10.3389/fcell.2021.704591
• Publication Date: 2021-07-15T18:25:19Z
• Authors: Guillermo Rodrígu...; Ana Casado-García; Marta Isidro-Hern...; Daniel Picard; Javier Raboso-Gal...; Silvia Alemán-Art...; Alberto Orfao; Oscar Blanco; Susana Riesco; Pablo Prieto-Matos; Francisco Javier ...; María Begoña Garc...; Hanno Hock; Tariq Enver; Isidro Sanchez-Ga...; Carolina Vicente-...
• Keywords: ETV6; RUNX1; Lymphopoiesis

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