About 10 children per year in the Netherlands are diagnosed with T-cell lymphoblastic lymphoma (T-LBL). Four out of five children are cured. However in one in five children the disease returns. They have the high-risk variant of the disease. For these children, the prognosis is poor. More research into this variant is therefore important.
Innovative RNA data analyses
Much is still unknown about the origin and development of this form of lymphoma. Researchers at the Máxima Center therefore investigated the biology of this disease. For example, they examined what happens in the RNA in children with T-LBL. The RNA is the translation of the DNA code. In order to make the correct diagnosis, the Laboratory for Pediatric Oncology analyzes the RNA of every child under treatment at the Máxima Center. These data are stored after child and parent consent and are available, upon request, to researchers from the Máxima Center.
PhD student Emma Kroeze and bioinformatician Michelle Kleisman examined the data of 29 children with T-LBL treated at Máxima between 2018 and 2023. They did this under the guidance of research group leader Prof. Dr. Roland Kuiper and Dr. Jan Loeffen, pediatric oncologist specializing in lymphoma treatment. Kroeze: 'It was already possible, via DNA changes in the NOTCH1 and/or FBXW7 gene, to identify the low-risk variant in children. We started looking for similarities in the RNA to be able to determine the high-risk variant as well.'
Using innovative data analysis, Kleisman looked for similarities between the genetic data and the different tumors. Thus, the researchers discovered three, previously unknown, NOTCH1 gene fusions that characterize the high-risk group of children. Kleisman: 'To learn more about T-LBL, I looked specifically at variations within the NOTCH1 gene. As a result, we discovered NOTCH1 gene fusions that we would not be able to find with conventional analyses. This study clearly shows how important data comparisons are to making strides within pediatric oncology research.'
In addition, all six children with this variant had significantly elevated CCL17 levels, also known as TARC levels, in their blood. Kroeze: 'Children with T-LBL with the gene fusions found therefore have a much higher chance of recurrence of the disease. And we can predict this even before treatment by measuring the CCL17 value in the blood.'
Clinical application
Now that a biomarker is known from the research, translation to the clinic is the next step. Dr. Jan Loeffen, pediatric oncologist specializing in the treatment of lymphoma: 'It is of great value that before treatment starts we know through blood analysis which child falls into the high-risk group. After all, it brings personalized treatment one step closer. For instance, we think that a different treatment is needed for this group.'
The next step, therefore, is to work with pediatric oncologists from across Europe to determine the most appropriate treatment for this high-risk group of children. In addition, a larger group of children will be studied in European studies. Loeffen: 'This was a relatively small study. However, the results are clear enough to start conversations about adjustments in the clinic. This study is a wonderful example of the Máxima Center as a research hospital. Because we treat all Dutch children with cancer in Utrecht, research in the lab accelerates, resulting in better treatments.'
This research was made possible thanks to funding from KiKa.
The scientific publication can be found here: Kroeze E, Kleisman MM, Kester LA, et al. NOTCH1 fusions in pediatric T-cell lymphoblastic lymphoma: A high-risk subgroup with CCL17 (TARC) levels as diagnostic biomarker. Hemasphere. 2024 Jun 27;8(7):e117.