Data from Infection Exposure Promotes <i>ETV6-RUNX1</i> Precursor B-cell Leukemia via Impaired H3K4 Demethylases

• DOI: 10.1158/0008-5472.c.6509159
• Publication Date: 2023-03-31T02:25:10Z
• Authors: Guillermo Rodrígu...; Julia Hauer; Alberto Martín-Lo...; Daniel Schäfer; Christoph Bartenh...; Idoia García-Ramírez; Franziska Auer; Inés González-Her...; Lucia Ruiz-Roca; Michael Gombert; Vera Okpanyi; Ute Fischer; Cai Chen; Martin Dugas; Sanil Bhatia; René Martin Linka; Marta Garcia-Suquia; María Victoria Ra...; Angel Garcia-Sanchez; Oscar Blanco; Maria Begoña Garc...; Francisco Javier ...; César Cobaleda; Diego Alonso-López; Javier De Las Rivas; Markus Müschen; Carolina Vicente-...; Isidro Sánchez-Ga...; Arndt Borkhardt

<div>Abstract<p><i>ETV6-RUNX1</i> is associated with the most common subtype of childhood leukemia. As few <i>ETV6-RUNX1</i> 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 <i>in vivo</i> genetic evidence mechanistically connecting preleukemic <i>ETV6-RUNX1</i> expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, <i>ETV6-RUNX1</i> conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic <i>ETV6-RUNX1</i> pro/preB cells showed high <i>Rag1/2</i> expression, known for human <i>ETV6-RUNX1</i> pB-ALL. Murine and human <i>ETV6-RUNX1</i> pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (<i>KDM</i>) 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 <i>ETV6-RUNX1</i> preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. <i>Cancer Res; 77(16); 4365–77. ©2017 AACR</i>.</p></div>