Group leader: Prof.dr. Monique L. den Boer
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:
Elucidating mechanisms by which leukemic cells can escape from chemotherapy and finding ways to modulate this.
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 inhibitors 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 (VAGABOND consortium). 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.
Applications for scientific internships (MD, MSc, HLO) can be directed to email@example.com
- ASH Abstract Achievement Award. Anna Østergaard, 2022.
- ODAS award for pediatric oncology research, bridging science and clinics. Monique den Boer, 2019.
- ZonMW Open Science Impuls: award for open science, data stewardship, transparency in research. Monique den Boer, 2019.
- Horizon COFUND, Máxima Butterfly program to train and educate 28 PhD students. Program leader M.Kool (Máxima). Monique den Boer, group leader for ALL-research, 2023-2026
- Multi-omics data integration in B-cell precursor ALL and beyond. KiTZ-Máxima Research Fund, 2023-2025
- Towards safe therapy reduction in non-high risk B-cell acute lymphoblastic leukemia (with Pieters group). Máxima Foundation Toptalent grant awarded to Anna Østergaard, 2021-2024
- Identifying targets to modulate CAR-T cell functionality using advanced 3D co-culture and imaging technologies: towards better survival of pediatric BCP-ALL patients (with Friso Calkoen, Nierkens group, Rios group, and Pieters group). ODAS Foundation, 2021-2024
- ITN-VAGABOND, Validation of Actionable Genomic Aberrations in a pediatric Oncology Network for Doctorate students. Program leader: J. Molenaar (Máxima). Monique den Boer, WP4 leader-ALL drug response profiling. EU-HORIZON-CURIE innovative training network grant (11 beneficiaries from 8 EU countries, 15 PhD students total), 2021-2024
- Oncode clinical proof of concept grant “International concerted action on precision medicines trials in children with relapsed and refractory leukemia/lymphoma (with Trial and Data Center). Oncode cPoC grant, 2020-2022
- The apparent Janus-faced nature of ALL and AML (with Josef Vormoor). KiKa-Máxima grant, 2019-2023
- Unrestricted personal grant as part of a nationwide initiative supported by 3 Ministries, ‘NWO, ZonMW and KWF to support innovation in research). The Oncode Institute, 2018-2022
- Challenging the dogmatic use of ABL1-directed tyrosine kinase inhibitors in BCR-ABL1-positive acute lymphoblastic leukemia. KWF and Alpe d’HuZes Unique High Risk project, 2018-2020
- MRD4ALL: Towards minimal residual disease stratification in each child with acute lymphoblastic leukemia. Kika Foundation, 2018-2019
- Beating chromosome 21: small chromosome, large consequences in acute lymphoblastic leukemia. Dutch Cancer Society, 2017-2020
- A humanized bone marrow micro-environment mouse model for acute lymphoblastic leukaemia. Kika foundation, 2017-2018
- Identification of new prognostic genetic risk markers for high hyperdiploid childhood acute lymphoblastic leukemia. KiKa foundation, 2017-2019
- Precision medicines in leukemia (collaborative study with St. Jude’s Children’s Research Hospital, Memphis, TN USA. NIH program grant, 2015-2020
- Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort study. Den Boer ML, Cario G, Moorman AV, Boer JM, de Groot-Kruseman HA, Fiocco M, Escherich G, Imamura T, Yeoh A, Sutton R, Dalla-Pozza L, Kiyokawa N, Schrappe M, Roberts KG, Mullighan CG, Hunger SP, Vora A, Attarbaschi A, Zaliova M, Elitzur S, Cazzaniga G, Biondi A, Loh ML, Pieters R; Ponte di Legno Childhood ALL Working Group. Lancet Haematol. 2021 Jan;8(1):e55-e66. PMID: 33357483.
- Autophagy Inhibition as a potential future targeted therapy for ETV6-RUNX1 driven B-cell Precursor Acute Lymphoblastic Leukaemia. Polak R, Bierings MB, Van der Leije CS, Sanders MA, Roovers O, Marchante JRM, Cornelissen JJ, Pieters R, Den Boer ML*, Buitenhuis M*. * Shared senior authorship. Haematologica. 2019 Apr;104(4):738-748. PMID: 30381299
- RAS pathway mutations as a predictive biomarker for treatment adaptation in pediatric B-cell precursor acute lymphoblastic leukemia. Jerchel IS, Hoogkamer AQ, Ariës IM, Steeghs EMP, Boer JM, Besselink NJM, Boeree A, van de Ven C, de Groot-Kruseman HA, de Haas V, Horstmann MA, Escherich G, Zwaan CM, Cuppen E, Koudijs MJ, Pieters R, den Boer ML. Leukemia. 2018 32(4):931-940. PMID: 28972594.
- B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment. Polak R*, de Rooij B*, Pieters R, Den Boer ML. Blood. 126(21): 2404-2414 (2015). PMID: 26297738.
- Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Van der Veer A, Waanders E, Pieters R, Willemse ME, Van Reijmersdal SV, Russell LJ, Harrison CJ, Evans WE, Van der Velden VHJ, Hoogerbrugge PM, Van Leeuwen F, Escherich G, Horstmann MA, Mohammadi Khankahdani L, Rizopoulos D, De Groot-Kruseman HA, Sonneveld E, Kuiper RP*, Den Boer ML*. Blood 122, 2622-2629 (2013). PMID: 19138562