A study in Nature Genetics by an international team of researchers provides new insights into acute lymphoblastic leukemia (ALL) in children. There are various forms of the disease, which also respond differently to therapy. These researchers decoded the molecular characteristics of an ALL subtype that has so far been aggressive and incurable, information that now suggest new options for therapy.
The study, now online ahead of print (doi:10.1038/ng.3362), involves the aggressive ALL subtype associated with at (17;19) chromosomal translocation, which occurs due to breakage and aberrant fusion of genetic material in the tumor cells, resulting in the formation of a new oncogenic protein encoded by the genes TCF3 and HLF (TCF3-HLF-positive leukemia cells).
“Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines, and agents in clinical development,” the researchers wrote, led by Ute Fischer, MD, of Heinrich Heine University in Germany.
“Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.”
The team, from Germany, Switzerland, France, the U.K., Italy, Austria, Turkey, China, and the Czech Republic, also collaborated with Alacris Theranostics GmbH, which has conducted an in-depth analysis of the molecular features of the t(17; 19) ALL subtype.
As explained in a news release, the consortium team decoded the genome of the leukemic cells using bioinformatics methods and found genetic aberrations in addition to the known translocation.
“We are glad that we could contribute to this important project with genomic data analysis of leukemia cells to unravel some of the molecular changes in this disease,” said Alacris CEO Bodo Lange, PhD.
The expression profile of the cancer cells was deciphered with RNA sequencing, a focus of research of another of the coauthors, Marie-Laure Yaspo, PhD, of Max Planck Institute for Molecular Genetics in Berlin.
Relevant Molecular Mechanisms
“The interplay between the fused TCF3-HLF oncogenic protein, additional DNA changes, and altered gene expression program leads to a re-programming of leukemic cells to an early, stem-cell like developmental stage, although the phenotypic appearance of the cells remains similar,” she said.
“This technique provides a quantitative read-out of the actual genetic program occurring in the cancer cells, which allowed us to uncover relevant molecular mechanisms cooperating to promote tumorigenesis, and identify possible druggable targets. These findings could be achieved only through analysis of the messenger RNAs.”
The project was funded by the German Federal Office for Radiation Protection via the environmental research program of the German Federal Environment Ministry and by the Swiss National Science Foundation.