Infection exposure promotes ETV6-RUNX1 precursor B-cell leukemia via impaired H3K4 demethylases

Guillermo Rodríguez-Hernández, Julia Hauer, Alberto Martín-Lorenzo, Daniel Schäfer, Christoph Bartenhagen, Idoia García-Ramírez, Franziska Auer, Inés Gonzalez-Herrero, Lucia Ruiz-Roca, Michael Gombert, Vera Okpanyi, Ute Fischer, Cai Chen, Martin Dugas, Sanil Bhatia, René Martin Linka, Marta Garcia-Suquia, María Victoria Rascón-Trincado, Angel Garcia-Sanchez, Oscar BlancoMaria Begoña García-Cenador, Francisco Javier García-Criado, César Cobaleda, Diego Alonso-López, Javier De Las Rivas, Markus Müschen, Carolina Vicente-Dueñas, Isidro Sánchez-García, Arndt Borkhardt

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches.

Original languageEnglish
Pages (from-to)4365-4377
Number of pages13
JournalCancer Research
Volume77
Issue number16
DOIs
StatePublished - 15 Aug 2017
Externally publishedYes

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