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Cancer Res. 2017 Aug 15;77(16):4365-4377. doi: 10.1158/0008-5472.CAN-17-0701. Epub 2017 Jun 19.

Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases.

Author information

1
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.
2
Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
3
Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany.
4
Department of Computer Science, Bonn-Rhein-Sieg University of Applied Sciences, Sankt Augustin, Germany.
5
Departamento de Ciencias Biomédicas y del Diagnóstico, Área de Obstetricia y Ginecología, HUS-Universidad de Salamanca, Salamanca, Spain.
6
IBSAL, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain.
7
Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain.
8
Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
9
Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.
10
Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
11
Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
12
Department of Laboratory Medicine, University of California San Francisco, San Francisco, California.
13
Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany. Arndt.Borkhardt@med.uni-duesseldorf.de.

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. Cancer Res; 77(16); 4365-77. ©2017 AACR.

PMID:
28630052
DOI:
10.1158/0008-5472.CAN-17-0701
[Indexed for MEDLINE]
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