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RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia

Elli Papaemmanuil, E., Inmaculada Rapado, I., Yilong Li, Y., Potter, N.E., Wedge, D.C., Tubio, J., Alexandrov, L.B., Van Loo, P., Cooke, S.L., Marshall, J., Martincorena, I., Hinton, J., Gundem, G., van Delft, F.W., Nik-Zainal, S., Jones, D.R., Ramakrishna, M., Titley, I., Stebbings, L., Leroy, C., Menzies, A., Gamble, J., Robinson, B., Mudie, L., Raine, K., O’Meara, S., Teague, J.W., Butler, A.P., Cazzaniga, G., Biondi, A., Zuna, J., Kempski, H., Muschen, M., Ford, A.M., Stratton, M.R., Greaves, M., Campbell, P.J.

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction; ~30-fold enrichment at promoters and enhancers of genes actively transcribed in B-cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single cell tracking shows that this mechanism is active throughout leukemic evolution with evidence of localized clustering and re-iterated deletions. Integration of point mutation and rearrangement data identifies ATF7IP and MGA as two new tumor suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B-cell differentiation.

Citation

Elli Papaemmanuil, E., Inmaculada Rapado, I., Yilong Li, Y., Potter, N.E., Wedge, D.C., Tubio, J., Alexandrov, L.B., Van Loo, P., Cooke, S.L., Marshall, J., Martincorena, I., Hinton, J., Gundem, G., van Delft, F.W., Nik-Zainal, S., Jones, D.R., Ramakrishna, M., Titley, I., Stebbings, L., Leroy, C., Menzies, A., Gamble, J., Robinson, B., Mudie, L., Raine, K., O’Meara, S., Teague, J.W., Butler, A.P., Cazzaniga, G., Biondi, A., Zuna, J., Kempski, H., Muschen, M., Ford, A.M., Stratton, M.R., Greaves, M., Campbell, P.J. "RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia" Nature Genetics (2014): 116–25