Acute lymphoblastic leukemia (ALL) frequently develops between the age of two and three. This leukemia has various forms, which differ through certain changes in the genetic material of the leukemia cells. A team of scientists involved in a joint international project headed by Jean-Pierre Bourquin, a pediatric oncologist from the University Children’s Hospital Zurich, and Martin Stanulla, a professor at Hannover Medical School, has now succeeded in decoding the genome of a currently incurable sub-type of acute lymphoblastic leukemia.
The two genes TCF3 and HLF are known to be fused together incorrectly in this subtype of acute lymphoblastic leukemia. This change in the genetic code confers resistance to all current treatments. The scientists have now discovered that other DNA areas are also changed in addition to the two incorrectly fused genes.
A wolf in sheep’s clothing
Defective genes that control the development of highly specific blood defense cells, so-called B-lymphocytes, and promote cell growth were altered in the leukemia cells studied. The interplay between the defective fusion of TCF3 and HLF triggers a previously underestimated reprograming of the leukemia cells to a very early, stem-cell-like developmental stage, which can not be detected by readily by current diagnostic test. “– a kind of “wolf in sheep’s clothing”.
The group of Jean-Pierre Bourquin developed a humanized mouse model at the University Children’s Hospital in Zurich that enables researchers to explore leukemias in conditions that are very similar to the situations encountered in humans. “In other words, we created a model to accelerate the discovery of more personalized treatment options,” explains Bourquin. The human leukemia cells growing in the mouse retain the crucial genetic changes and, according to Bourquin, therefore constitute a realistic possibility to examine new courses of therapy in a patient-oriented manner.
Promising drug tests
On this basis, the Zurich researchers tested hundreds of novel drugs. Some of them, which are still undergoing further clinical development, displayed a very positive effect. One such drug is Venetoclax, which specifically targets the protein BCL2 relevant for the programmed cell death and already worked for other cancer strains.
In the mouse model, Venetoclax triggered a significant decline in the disease, followed by lengthy phases without any signs of the disease if administered with conventional chemotherapy for leukemia. “Further studies are now needed to test how the results of our study might be used for therapeutic possibilities,” says Bourquin. “Our work just goes to show the great potential of coordinated, interdisciplinary research approaches involving cutting-edge technological possibilities for cancer research,” he concludes.
The development of new courses of therapy in the humanized leukemia model was supported by the Swiss National Science Foundation and the University of Zurich’s clinical research focus program “Human Hemato-Lymphatic Diseases”. The genetic studies were funded by the German Federal Office for Radiation Protection via the environmental research program of the German Federal Environment Ministry.
Ute Fischer et.al. Genomics and drug profiling of fatal TCF3-HLF−positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. 27 July, 2015. Nature Genetics. doi:10.1038/ng.3362