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

  1. Rodríguez-Hernández, Guillermo 12
  2. Casado-García, Ana 12
  3. Isidro-Hernández, Marta 12
  4. Picard, Daniel 3
  5. Raboso-Gallego, Javier 12
  6. Alemán-Arteaga, Silvia 12
  7. Orfao, Alberto 12
  8. Blanco, Oscar 24
  9. Riesco, Susana 25
  10. Prieto-Matos, Pablo 25
  11. García Criado, Francisco Javier 26
  12. García Cenador, María Begoña 26
  13. Hock, Hanno 7
  14. Enver, Tariq 8
  15. Sanchez-Garcia, Isidro 12
  16. Vicente-Dueñas, Carolina 25
  1. 1 Universidad de Salamanca
    info

    Universidad de Salamanca

    Salamanca, España

    ROR https://ror.org/02f40zc51

  2. 2 Institute for Biomedical Research of Salamanca, Salamanca, Spain
  3. 3 Heinrich Heine University Düsseldorf
    info

    Heinrich Heine University Düsseldorf

    Düsseldorf, Alemania

    ROR https://ror.org/024z2rq82

  4. 4 Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain
  5. 5 Department of Pediatrics, Hospital Universitario de Salamanca, Salamanca, Spain
  6. 6 Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain
  7. 7 Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, and Harvard Stem Cell Institute, Boston, MA, United States
  8. 8 Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom
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Revista:
Frontiers in Cell and Developmental Biology

ISSN: 2296-634X

Año de publicación: 2021

Volumen: 9

Tipo: Artículo

DOI: 10.3389/FCELL.2021.704591 GOOGLE SCHOLAR

Otras publicaciones en: Frontiers in Cell and Developmental Biology

Resumen

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.

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