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Den Boer group

The Den Boer group focuses on the discovery of new (genetic) lesions and targets for precision medicines (including immune-therapeutics) to improve the clinical outcome for children with B-cell precursor acute lymphoblastic leukemia. We have expertise in so-called pathobiological studies addressing which (combination of) genetic lesions characterize leukemia, how these lesions mechanistically contribute to therapy resistance and how leukemic cells manipulate the bone marrow niche for its own benefit. Our work is a key-example of research bridging lab and clinics.

PI: Prof.dr. Monique L. den Boer

 

"Leukemia cannot be prevented, so let’s beat the leukemic cells at their Achilles’ heel." Prof.dr. Monique den Boer - PI

Our mission:

To provide solid laboratory evidence that the diagnosis and treatment of ALL can be more tailored, shorter and with less side-effects if directed towards biological targets expressed by leukemic cells and against leukemia-driven changes in the bone marrow niche.

Main topics of studies:

 

Summary of recent activities:

Our program consists of two research lines (oncogenomics and leukemic niche) which are tightly connected to treatment protocols for newly diagnosed ALL (a.o. ALLtogether, EsPhALL) and to new drug development programs of the trial and data center of the Princess Máxima Center and the Innovative Therapies for Children with Cancer (ITCC) consortium.

The oncogenomics research line focuses on the role of genetic abnormalities and deregulated (phospho)proteins in the pathobiology of pediatric B-cell precursor ALL in order to find new prognostic biomarkers and drugs with high efficacy and specificity.

In the recent past, we discovered a new high-risk type of pediatric ALL, i.e. BCR-ABL1-like ALL, by means of genomic studies (Den Boer, Lancet Oncology 2009). Following this discovery, genetic lesions characterizing this new high-risk subtype were implemented as diagnostic markers in new treatment protocols: Treatment was extended for patients with deletions in the Ikaros gene (DCOG ALL-11 study) and the tyrosine kinase inhibitor Imatinib was added to the induction therapy of patients with lesions in ABL-class family genes (ALLtogether-1 study).

In addition, our oncogenomics studies revealed lesions in Ras-mediated proliferation pathways, JAK-STAT-mediated growth factor receptor signaling and autophagy-mediated detoxifying mechanisms which may all serve as targets for specific inhibitors. Resistance to the spearhead drug prednisone was shown to be caused by increased glucose consumption and Ras-pathway mutations, which could be reversed by specific glycolysis and MEK/ERK inhibitors such as Trametinib.

Our leukemic niche research line addresses the interaction between leukemic cells and the bone marrow microenvironment. We discovered a pro-survival communication mechanism induced by tunneling nanotubes, which were shown to increase the viability of leukemic cells and to reduce the sensitivity of leukemic cells to chemotherapeutic drugs. In ongoing research we unravel the molecules driving resistance of leukemic cells in the bone marrow niche (Oncode program grant, core-funding Kika). This work is of high interest to tackle the way leukemic cells escape from immunotherapies like CAR-T, antibody-directed cellular cytotoxicity (e.g.blinatumomab) and drug-conjugated antibodies (e.g. inotuzumab).

As part of both research lines, we also study the potential synergistic effect of new precision medicines in combination with conventional drugs, since this gives a rationale how to combine these new drugs with yet established chemotherapy. In addition, we develop 3D leukemic niche models, which are of high interest to image the effect of (immunomodulatory) drugs in the interaction between leukemic cells, healthy immune cells and the bone marrow niche. Our combined knowledge about the dynamics in the (leukemic) bone marrow niche, drug resistance and pathobiology/genetic lesions in leukemic cells is unique and may lead to innovative ways to treat childhood ALL.

Other links:

https://mediator.zonmw.nl/mediator-38/de-overzichtelijke-data-van-monique-den-boer

https://www.oncode.nl/news/stories/the-added-value-and-simplicity-of-data-management-the-how-the-why-and-what-sound-data-management-can-bring-to-your-lab

https://www.oncode.nl/research/groups/monique-den-boer-group 

Applications for scientific internships (MD, MSc, HLO) can be directed to m.l.denboer@prinsesmaximacentrum.nl 

Den Boer group