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Team IDs New Recurrent Fusions in ALL Cases in Adolescents, Young Adults

NEW YORK (GenomeWeb) – A University of Tokyo-led team reported today in Nature Genetics that it has identified a recurrent fusion that seems to be specific to B cell acute lymphoblastic leukemia (ALL) samples from adolescents or young adults whose tumors are Philadelphia chromosome-free.

With the help of RNA sequencing on samples from 73 individuals between 15 and 39 years old with B-cell ALL, T-cell ALL, or ALL of unknown origin, the researchers tracked down a dozen new candidate fusions. The most common fusions — found in 10 samples from the discovery set — involved insertions of repeat sequences from a gene called DUX4 into the immunoglobulin IGH locus.

In subsequent testing, those fusions turned up exclusively in the adult and young adult cases, while recurrent fusions involving the ZNF384 or MEF2D genes seemed to occur in cases with a slightly broader age range. And the group's follow-up experiments in cell lines and mouse models hint that the DUX4-IGH fusion may prompt B-cell leukemia development in the B-cell lineage.

"DUX4 can become an oncogenic driver as a result of somatic chromosomal rearrangements," senior author Hiroyuki Mano, a cellular signaling researcher at the University of Tokyo, and co-authors wrote, adding that "[adolescent and young adult ALL] may be a clinical entity distinct from ALL at other ages."

The researchers used Illumina HiSeq 2000 or 2500 instruments to do RNA sequencing on bone marrow mononuclear cell samples from adolescent or young adult ALL cases missing the characteristic BCR-ABL1 fusion, or Philadelphia chromosome, that marks a subset of leukemia cases. These included 54 individuals with B-cell ALL, 18 with T-cell ALL, and one individual with ALL from an indeterminate white blood cell lineage.

By comparing the transcriptome patterns found in those samples to RNA sequences from three Philadelphia chromosome-positive cases and in blood cells from eight healthy volunteers, they narrowed in on 26 apparent fusion genes, including 12 not described previously.

Using a combination of RNA sequencing and RT-PCR, the team looked at the prevalence of the three most common new fusions, involving DUX4, ZNF384, or MEF2D, in 61 additional B-cell ALL cases without the BCR-ABL1 fusion. These included childhood cases occurring before the age of 14, adolescent-young adult cases, and cases in individuals over 40 years old.

While the DUX4 fusions turned up exclusively in adolescent and young adult cases, the researchers reported, the ZNF384 fusions were somewhat more common for cases in this age range. The MEF2D fusion was detected in a subset of both childhood cases and B-cell ALL cases diagnosed in the 15 to 39 year olds.

They saw a similar over-representation in DUX4 fusions within ALL cases in the adolescent-young adult age range when they scoured available transcriptome data from the TARGET study.

All told, the team's results suggest that roughly 40 percent of Philadelphia chromosome-negative B-cell ALL cases in adolescents or young adults contain fusions involving DUX4, ZNF384, or MEF2D. The broader gene expression profiles of tumors with these fusions did not resemble those found in Philadelphia chromosome-like tumors, the group noted, and tumors with DUX4 or ZNF384 fusions appeared to correspond with somewhat better disease-free survival times.

When they focused in on the DUX4 fusions, for example, the researchers found that so-called D4Z4 repeats from this gene often get translocated into the genes in the IGH locus, producing a fusion that seemed to prompt pro-B-cell transformation toward leukemia through multiple molecular mechanisms, according to their follow-up studies on human and mouse cell lines and mouse models of disease.

"Identification of the downstream effectors of these oncogenic drivers could provide important information for the development of new treatment approaches to [adolescent and young adult ALL]," the study authors concluded.