Rodríguez-Hernández, Guillermo;
Casado-García, Ana;
Isidro-Hernández, Marta;
Picard, Daniel;
Raboso-Gallego, Javier;
Alemán-Arteaga, Silvia;
Orfao, Alberto;
... Vicente-Dueñas, Carolina; + view all
(2021)
The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia.
Frontiers in Cell and Developmental Biology
, 9
, Article 704591. 10.3389/fcell.2021.704591.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fcell.2021.704591 |
| Publisher version: | https://doi.org/10.3389/fcell.2021.704591 |
| Language: | English |
| Additional information: | © 2021 Rodríguez-Hernández, Casado-García, Isidro-Hernández, Picard, Raboso-Gallego, Alemán-Arteaga, Orfao, Blanco, Riesco, Prieto-Matos, García Criado, García Cenador, Hock, Enver, Sanchez-Garcia and Vicente-Dueñas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | transcription factors, B-cell, somatic, germline, childhood leukemia, mouse models |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10167258 |
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