Japanese Scientists Find Gene Fusion Driving B Cell Leukemia

In a new Nature Genetics paper, scientists from the University of Tokyo and several other Japanese institutes and hospitals present results of a sweeping study of gene fusions driving a form of leukemia in teenagers and young adults. They used SMRT Sequencing to validate the gene fusion.
“Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults” comes from lead author Takahiko Yasuda and senior author Hiroyuki Mano, along with many collaborators. The team embarked on the search for new oncogenes responsible for acute lymphoblastic leukemia (ALL) in subjects from 15 to 39 years of age because the mechanisms responsible for this cancer “remain largely elusive,” they write.
From a large RNA-seq analysis, they found frequent insertion of a D4Z4 repeat that includes the DUX4 gene into the IGH locus, creating a DUX4-IGH gene fusion that produces high expression levels of an aberrant form of DUX4. The scientists transplanted this gene fusion into mice, where it led to the generation of B cell leukemia. They report that fusion-driven oncogenes are more important for causing ALL in this age range than previously thought. “Our data thus show that DUX4 can become an oncogenic driver as a result of somatic chromosomal rearrangements and that [ALL in adolescents and young adults] may be a clinical entity distinct from ALL at other ages,” Yasuda et al. write.
The team used SMRT Sequencing to confirm the full sequence of the gene fusion, which could not be done with short-read sequencing. “Given that the average read length in our next-generation sequencing approach was 104 bp, it was difficult to determine how many copies of DUX4 had been inserted into the IGH locus,” they report. They performed whole genome sequencing of a B cell line cultured from a 19-year-old ALL patient, generating about 69 Gb of data.
“Our analysis confirmed that one full-length and one partial copy of D4Z4 were translocated to the IGH locus, accompanied by minor rearrangements within the IGHD2-15 and IGHVII-60-1 regions,” the scientists report. This figure shows SMRT Sequencing data confirming the presence of the DUX4-IGH gene fusion.
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