Photo courtesy of St. Jude
Children’s Research Hospital
Researchers say they have uncovered a unique paradigm of transcription factor deregulation in B-precursor acute lymphoblastic leukemia (B-ALL).
The team found that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-ALL that may comprise up to 8% of B-ALL cases.
The researchers reported these findings in Nature Genetics.
“Our work is motivated by a lack of information on the genetic basis of many B-ALL cases,” said study author Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“We discovered a distinct gene pattern in blood samples from some patients in our study and wanted to determine the underlying molecular events behind this signal.”
The researchers studied a group of 1913 B-ALL patients (including children, adolescents, and young adults) to understand the genetic basis of the disease.
Microarray and transcriptome sequencing revealed that 7.6% of these patients had the distinctive genetic profile the researchers wanted to characterize further.
“Our work revealed that, in this type of B-ALL, there is a sequence of molecular events that involves the interplay of 2 transcription factors,” Dr Mullighan said.
The team observed rearrangement of the gene DUX4 in all cases of this subtype of B-ALL, which resulted in high-level expression of DUX4. DUX4 was shown to bind to the ERG gene, leading to deregulated expression of ERG.
The deregulation of ERG compromised the function of ERG either by deleting part of the gene or by expressing another form of ERG—ERGalt. In both cases, loss of activity was observed for the ERG transcription factor, which led to leukemia.
“These results underscore that there is still more to be learned about the genetic changes in ALL, and that this knowledge can help refine treatment for patients,” said study author Stephen Hunger, MD, of the Children’s Hospital of Philadelphia in Pennsylvania.
The researchers hope identification of the relationships between the 2 transcription factors will lead to new diagnostic tests for patients. DUX4/ERG ALL is linked to favorable outcomes even when other detrimental genetic mutations are present.
Currently, only transcriptome or genome sequencing helps identify the DUX4 rearrangements. The researchers say other detection methods, such as fluorescence hybridization or karyotyping, are not sufficient to recognize genetic changes to DUX4.
