The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia
- Rodríguez-Hernández, Guillermo 12
- Casado-García, Ana 12
- Isidro-Hernández, Marta 12
- Picard, Daniel 3
- Raboso-Gallego, Javier 12
- Alemán-Arteaga, Silvia 12
- Orfao, Alberto 12
- Blanco, Oscar 24
- Riesco, Susana 25
- Prieto-Matos, Pablo 25
- García Criado, Francisco Javier 26
- García Cenador, María Begoña 26
- Hock, Hanno 7
- Enver, Tariq 8
- Sanchez-Garcia, Isidro 12
- Vicente-Dueñas, Carolina 25
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1
Universidad de Salamanca
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- 2 Institute for Biomedical Research of Salamanca, Salamanca, Spain
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3
Heinrich Heine University Düsseldorf
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- 4 Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain
- 5 Department of Pediatrics, Hospital Universitario de Salamanca, Salamanca, Spain
- 6 Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain
- 7 Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, and Harvard Stem Cell Institute, Boston, MA, United States
- 8 Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom
ISSN: 2296-634X
Año de publicación: 2021
Volumen: 9
Tipo: Artículo
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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