Fusions involving DUX4 and ZNF384 are specific drivers of adolescent and young adult ALL.

  • Major finding: Fusions involving DUX4 and ZNF384 are specific drivers of adolescent and young adult ALL.

  • Mechanism: The DUX4–IGH fusion results from a translocation that inserts D4Z4 repeats at the IGH locus.

  • Impact: Adolescent and young adult ALL may be a distinct clinical entity with unique therapeutic targets.

The oncogenic drivers of Philadelphia chromosome (Ph)–negative acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA; 15 to 39 years old) remain largely unknown. In an effort to identify specific drivers of AYA-ALL leukemogenesis, Yasuda and colleagues performed RNA sequencing in 73 patients with Ph AYA-ALL. Recurrent fusions involving DUX4, ZNF384, or MEF2D were identified; further RNA sequencing of a validation cohort indicated that DUX4 and ZNF384 fusions were specific to AYA-ALL, whereas MEF2D fusions were found in AYA-ALL as well as childhood ALL. DUX4, ZNF384, and MEF2D fusions were found to be mutually exclusive, and specific to Ph ALL. The DUX4 gene is located in a subtelomeric region of chromosome 4q within D4Z4 repeats, and in a subset of AYA-ALL cases, D4Z4 repeats were translocated to the IGH locus on chromosome 14. Unlike other leukemic translocations, this somatic rearrangement resulted from an insertion rather than a balanced chromosomal translocation, and resulted in fusion of the 3′ end of DUX4 to IGH or another gene, causing increased expression of DUX4, a homeobox-containing protein. The DUX4 fusions were sufficient to transform NIH3T3 cells, and knockdown of DUX4 suppressed proliferation of B-ALL cells. DUX4–IGH-expressing pro-B cells were leukemogenic and able to be serially transplanted, suggesting that DUX4–IGH promotes self-renewal. EP300–ZNF384 also induced leukemia, albeit with a longer latency period. MEF2D–BCL9 had a low penetrance, but gave rise to leukemia in approximately half of mice. Taken together, these findings identify fusion oncogenes that drive AYA-ALL and distinguish it from ALLs at other ages, and suggest that chromosomal rearrangements in DUX4, ZNF384, or MEF2D account for approximately 40% of Ph B-cell AYA-ALL cases. Further, identification of downstream pathways could identify therapeutic targets and provide insight into how AYA-ALL arises.

Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F, Kojima S, Ueno T, et al. Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nat Genet 2016 Mar 28 [Epub ahead of print].