A study found that deregulation of homeobox transcription factor genes underlies a subtype of precursor B-cell acute lymphoblastic leukemia.
Deregulation of homeobox transcription factor genes underlies a subtype of precursor B-cell acute lymphoblastic leukemia (B-ALL), researchers reported in Nature Genetics. The findings identify a “unique mechanism” for how transcription factors promote leukemia.
“Our work revealed that in this type of B-ALL, there is a sequence of molecular events that involves the interplay of two transcription factors,” said corresponding coauthor Charles G. Mullighan, MBBS, MSc, MD, of the department of pathology at St. Jude Children’s Research Hospital in Memphis. The study team included researchers at the St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project collaboration and the Children’s Oncology Group.
The researchers conducted microarray and transcriptome gene expression analysis for 1,913 patients (including 1,347 children and 395 adolescents) diagnosed with B-ALL. Sequencing data revealed a “distinct gene expression profile” involving DUX4 gene rearrangements and ERG gene deletion. This gene deregulation profile was present in 7.6% of B-ALL patients overall, 5.2% of patients with standard-risk childhood B-ALL, 9.4% of children with high-risk B-ALL, 10.2% of adolescents with B-ALL, and 5.4% of patients with adult ALL.
DUX4 gene rearrangements and DUX4 upregulation were found in all cases of this subtype of ALL. DUX4 transcription factor protein binds to the ERG transcription factor gene, the authors found.
“Eighty-five (55.6%) of these cases had focal deletions of ERG on chromosome 21q22.3…which were not observed in other B-ALL or T-ALL cases,” the authors reported. The team also identified patients with an ERG gene variant, ERGalt, which also led to a loss of activity for ERG protein.
ERG and DUX4 deregulation led to loss of activity for ERG protein, leading to leukemia, the authors noted.
“Our data reveal that a genetic rearrangement of DUX4 is present in all cases for patients with the distinct gene expression profile identified in our study,” said coauthor Li Ding, PhD, of the McDonnell Genome Institute at the Washington University School of Medicine in St. Louis, in a press release. “The genetic rearrangement of DUX4 is a clonal event that is acquired early in the development of leukemia.”
ERG encodes the ETS-family transcription factor v-ets avian erythroblastosis virus E26 oncogene. It is suspected to play a role in regulating B-lymphoid development but its role in ALL is not known. ERG rearrangements are common in prostate carcinoma, and ERG upregulation is associated with poor prognosis among patients with acute myeloid leukemia.
“ERG has a key role in hematopoietic differentiation, megakaryopoiesis, and megakaryoblastic leukemia associated with Down syndrome,” the authors noted.
ALL represents approximately 30% of childhood cancers, and B-ALL is the most common form of ALL, representing 80% of these malignancies. The DUX4/ERG-deregulated subtype of B-ALL represents 7% of these malignancies.