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

Guillermo Rodríguez-Hernández1,2, Julia Hauer3, Alberto Martín-Lorenzo1,2

  • 1Experimental 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.

Cancer Research
|June 21, 2017
PubMed

Insights

ETV6-RUNX1 gene fusions in stem cells increase childhood leukemia risk after infections. KDM gene alterations drive leukemia development and RAG off-target cleavage, offering new therapeutic targets.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ETV6-RUNX1 fusion is linked to childhood leukemia, but most carriers don't develop it.
  • Infection exposure is a suspected factor in leukemia development, suggested by time-space clusters.
  • The genetic mechanisms linking preleukemic ETV6-RUNX1 and infection to leukemia are unclear.

Purpose of the Study:

  • To investigate the mechanistic link between preleukemic ETV6-RUNX1 expression in hematopoietic stem cells and postnatal infections.
  • To understand the genetic basis for the development of precursor B-cell acute lymphoblastic leukemia (pB-ALL) in ETV6-RUNX1 carriers.
  • To identify molecular mechanisms driving clonal evolution from preleukemic to overt leukemia.

Main Methods:

  • Developed an in vivo model to study ETV6-RUNX1 in hematopoietic stem/progenitor cells.
  • Analyzed gene expression (Rag1/2) in murine preleukemic cells.
  • Performed genomic alteration analysis in murine and human ETV6-RUNX1 pB-ALL.
  • Investigated the role of KDM family genes, specifically KDM5C loss of function, and its effect on H3K4me3 and RAG2 interaction.

Main Results:

  • ETV6-RUNX1 conferred a low risk of pB-ALL after pathogen exposure in the model, mirroring human incidence.
  • Murine and human ETV6-RUNX1 pB-ALL showed high Rag1/2 expression and recurrent genomic alterations, particularly in KDM family genes.
  • KDM5C loss of function increased H3K4me3 levels, facilitating RAG2 interaction and recombination activity.

Conclusions:

  • Alterations in KDM family members are a disease-driving mechanism in ETV6-RUNX1-associated pB-ALL.
  • These KDM alterations explain RAG off-target cleavage observed in human leukemia.
  • The study elucidates the genetic basis for clonal evolution to pB-ALL post-infection and suggests novel therapeutic strategies.

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