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A RAG driver on the road to pediatric ALL

Nature Genetics volume 46, pages 96–98 (2014)Cite this article

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Genomic aberrations affecting genes in B cell differentiation are hallmarks of B-precursor acute lymphoblastic leukemia (ALL). A new whole-genome sequencing study of ETV6-RUNX1–positive ALL has now identified RAG-mediated recombination, which specifically targets genes and regulatory elements active during B cell differentiation, as the underlying mechanism.

B-precursor ALL is the most frequent malignancy in children and is characterized by the accumulation of immature B lymphocytes in the bone marrow. B-precursor ALL is classified into subtypes by cytogenetic abnormalities, including aneuploidies and recurrent chromosomal translocations, each with a different clinical outcome1. These subtype-specific cytogenetic aberrations are generally considered to be the initiating events in leukemia development, with a limited number of additional mutations required for disease emergence and progression. High-resolution genomic profiling uncovered submicroscopic copy number abnormalities, most of which affected single genes involved in B cell differentiation, in virtually all ALL subtypes2,3. These findings suggested that a block in B cell differentiation is one of the major events required for leukemia progression. For a number of these lesions, including deletions in IKZF1, CDKN2A, CDKN2B and BTG1, the surrounding breakpoints cluster between leukemic samples and carry cryptic recognition sequences for V(D)J recombination. These observations suggest a possible role for illegitimate, off-target activity of the RAG recombinase, a complex encoded by recombination-activating genes 1 and 2 (RAG1 and RAG2). On page 116 of this issue, Peter Campbell, Mel Greaves and colleagues present the complete genomic landscape of ETV6-RUNX1–positive ALL and show that RAG-mediated recombination is the driving mechanism in the progression of this ALL subtype4.

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Figure 1: Off-target RAG-mediated recombination in ETV6-RUNX1–positive ALL predominantly occurs at RSS-like motifs (gray triangles) in accessible, H3K4me3-marked (yellow pentagons) open chromatin.

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Authors and Affiliations

  1. Roland P. Kuiper and Esmé Waanders are affiliated with the Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands, and with the Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.,

    Roland P Kuiper & Esmé Waanders

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  1. Roland P Kuiper
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  2. Esmé Waanders
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Correspondence to Roland P Kuiper.

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The authors declare no competing financial interests.

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Kuiper, R., Waanders, E. A RAG driver on the road to pediatric ALL. Nat Genet 46, 96–98 (2014). https://doi.org/10.1038/ng.2879

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