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

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

doi:10.3389/fcell.2021.704591

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.

Highlights

Despite the enormous increase in tumor biology knowledge over the last four decades, the prevention of cancer development is still a distant goal
We recently demonstrated in mice that natural infection exposure can trigger oncogenic secondary hits, leading to the transformation of susceptible ETV6-RUNX1+ preleukemic cells and the emergence of B-cell acute lymphoblastic leukemia (B-acute lymphoblastic leukemia (ALL)) (Rodriguez-Hernandez et al, 2017a)
Our findings demonstrated that ETV6-RUNX1-associated B-ALL does not originate in the committed B-cell compartment

Summary

Introduction

Despite the enormous increase in tumor biology knowledge over the last four decades, the prevention of cancer development is still a distant goal. Childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent preleukemic chromosomal translocations that usually occur before birth (Mori et al, 2002; Greaves, 2018). The fusion gene is present in 1–5% of newborn children, but the actual incidence of ETV6-RUNX1+ B-ALL is much lower (0.0001%) (Mori et al, 2002; Schafer et al, 2018). The ETV6-RUNX1 fusion gene confers a low risk of developing B-ALL and presents only a first oncogenic event (“first hit”) in the process of leukemogenesis. A preleukemic clone is created, which requires secondary postnatal genetic aberrations for leukemic transformation (Swaminathan et al, 2015; Greaves, 2018)

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Conclusion