Frontiers in Cell and Developmental Biology (Jul 2021)

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

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

DOI
https://doi.org/10.3389/fcell.2021.704591
Journal volume & issue
Vol. 9

Abstract

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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.

Keywords