Oncogenomics

The oncogenomics research line focuses on the role of genetic abnormalities that are unique for B-cell precursor ALL and the effect these genetic lesions have on intracellular processes by which these cells become malignant. The major aim is to optimize the diagnosis of leukemia in children in clinically relevant risk groups, in such a way that patients get the best treatment with the best choice of medicines that suits the specifics of their leukemia.

In the recent past, we discovered a new high-risk type of pediatric ALL, i.e. BCR::ABL1-like ALL (Den Boer, Lancet Oncology 2009). Following this discovery, intensive worldwide research resulted in the identification of lesions in several members of the ABL-class gene family. Nowadays, lesions in the ABL-class family are implemented as diagnostic markers that determines the intensity of the treatment because of the high risk of relapse (Den Boer, Lancet Haematology 2021). In addition, these patients now receive precision medicines that target the abnormal cells more specifically: the tyrosine kinase inhibitor Imatinib is added to the treatment as soon as the genetic lesion is identified in a patient as part of the European ALLTogether-1 protocol for newly diagnosed patients.

In addition, a second genetic lesion was identified, i.e. an abnormal IKZF1 gene, that predicted which patients would relapse from their disease soon after ending their 2 years chemotherapy. The regrowth of leukemia was successfully prevented by extending the treatment with an extra year for many patients (Pieters, Lancet Haematology 2023).

By virtue of new technological developments including next-generating sequencing, many new genetic lesions have been identified for which some have prognostic value (e.g. NUTM1 lesions in infant leukemia) and others can be used to redirect treatment with precision medicines (e.g. mutations in RAS-MEK-ERK and JAK-STAT mediated pathways that affect the proliferation of leukemic cells). In ongoing studies, combinations of new precision medicines and traditional chemotherapeutic drugs are investigated to find combinations that work synergistically. An example is the combination of the MEK-ERK inhibitor trametinib and prednisolone, one of the key components of chemotherapy for children with ALL (Jerchel, Leukemia 2018). Also the synergy between precision medicines that target intracellular proteins active in leukemic cells together with immunotherapy that targets proteins expressed at the cell surface of leukemic cells is being explored.