Group leader: Prof.dr. Monique L. den Boer
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:
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 children with acute lymphoblastic leukemia (ALL). These include therapies for newly diagnosed patients but also programs that focus on the development of new medicines and immunotherapies for children with ALL.
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.
Leukemic niche
Our leukemic niche research line addresses the interaction between leukemic cells and the bone marrow microenvironment. We discovered a pro-survival communication mechanism which depends on direct contact between leukemic cells and the bone marrow support cells. Together this creates an ALL-educated niche in which stromal support cells are being instructed to produce pro-leukemic factors that maintain the vitality of leukemic cells. The nature of these factors depends on the genomic lesions characterizing the leukemia, showcasing how the oncogenomic and leukemic niche research lines benefit from each other. E.g. ETV6::RUNX1 positive ALL cells elicited an interferon α/β response in stromal support cells that most likely has immune-modulating effect in the local bone marrow microenvironment (Smeets, Haematologica 2024). This latter is part of ongoing research and will result in knowledge about factors driving resistance of leukemic cells in the bone marrow niche. This work is also of high interest to tackle the way leukemic cells escape from immunotherapies like CAR-T and T-cell engaging antibodies (e.g.blinatumomab, but also to drug-conjugated antibodies (e.g. inotuzumab). To study the effect of the leukemic niche on response to immunotherapy we are developing 3D bone marrow models that are scalable and reproducible and can be used to study the effect of (immunomodulatory) drugs in the interaction between leukemic cells, healthy immune cells and the bone marrow supportive cells. 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 improve the treatment of children with 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
Applications for scientific internships (MD, MSc, HLO) can be directed to m.l.denboer@prinsesmaximacentrum.nl
- ASH Travel Award. Anna Østergaard, 2023.
- 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.
- Migration and recruitment of healthy immune cells and CAR-T cells to leukemic bone marrow. Health Holland -public-private-partnership in Life Sciences (LSHM-23064). Project Leader ML den Boer in liaison with Mimetas BV, 2024-2027
- Immune suppressive factors in the acute lymphoblastic leukemia-educated bone marrow niche and relevance to blinatumomab response. Project leaders: ML den Boer and C van de Ven. Kika foundation, 2024-2028.
- 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
Selection out of >180 peer-reviewed publications by ML den Boer and group members:
- Tyrosine kinase inhibitor response of ABL-class acute lymphoblastic leukemia: The role of kinase type and SH3 domain. Van Outersterp I, Tasian SK, Reichert CEJ, Boeree A, de Groot-Kruseman HA, Escherich G, Boer JM, Den Boer ML. Blood, 2024. PMID: 38394665 Functional study revealing that the efficacy of 3 different tyrosine kinase inhibitors depends on the type of ABL-class fusion.
- Tyrosine kinase inhibitor resistance in de novo BCR::ABL1-positive BCP-ALL beyond kinase domain mutations. Van Outersterp, I., J.M. Boer, C. van de Ven, C.E.J. Reichert, A. Boeree, B. Kruisinga, H.A. de Groot-Kruseman, G. Escherich, A. Sijs-Szabo, A.W. Rijneveld, M.L. den Boer. Blood Advances, 2024. PMID: 38386975 Functional study revealing that intrinsic mechanisms of resistance to tyrosine kinase inhibitors exists in previously untreated BCR::ABL1 positive leukemia.
- B-Cell Precursor Acute Lymphoblastic Leukemia elicits an Interferon-α/β response in Bone-Marrow derived Mesenchymal Stroma. Smeets MWE, Steeghs EMP, Orsel J, Stalpers F, Vermeeren MMP, Hoogkamer AQ, Veltman K, Nierkens S, van de Ven C, den Boer ML. Haematologica, 2024. PMID: 38426282. Functional study showing a specific effect of ETV6::RUNX1 positive ALL on the bone marrow microenvironment.
- Improved outcome for acute lymphoblastic leukemia by prolonging therapy for IKZF1 deletion and decreasing therapy for other risk groups. R, de Groot-Kruseman HA, Fiocco M, Verwer F, Van Overveld APJ, Sonneveld E, van der Velden VHJ, Beverloo HB, Bierings M, Dors N, de Haas V, Hoogerbrugge PM, Van der Sluis IM, Tissing WJE, Veening M, Boer JM, Den Boer ML. J Clin Oncol, 2023. PMID: 37459571., Example of bridging between clinics (Pieters, 1st author) and research (Den Boer, last author).
- 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. [IF 2021: 30.153] Example of bridging between clinics and research in an international setting.
- Minimal Residual Disease, Long-Term Outcome, and IKZF1 Deletions in Down Syndrome Acute Lymphoblastic Leukemia in a Matched Cohort Study. Michels N, Boer JM, Enshaei A, Sutton R, Heyman M, Ebert S, Fiocco M, de Groot-Kruseman HA, van der Velden VHJ, Barbany G, Escherich G, Vora A, Trahair T, Dalla-Pozza L, Pieters R, zur Stadt U, Schmiegelow K, Moorman AV, Zwaan CM, Den Boer ML. Lancet Haematol. 2021 Oct;8(10):e700-e710. PMID: 34560013. [IF 2021 30.153] Example of bridging between clinics and research in an international setting.
- 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. 2018 32(4):931-940. PMID: 28972594. Example of oncogenomics discovery study showing a high frequency of RAS-pathway alterations in ALL.
- B-cell precursor acute lymphoblastic leukemia cells use tunneling nanotubes to orchestrate their microenvironment. Polak R, de Rooij B, Pieters R, Den Boer ML. 2015 126(21): 2404-2414. PMID: 26297738. Example of functional study showing the importance of the bone marrow niche for the vitality of leukemic cells.
- 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*. Blood122, 2622-2629 (2013). PMID: 19138562 Validation of unfavorable prognosis for BCR-ABL1-like ALL in 3 independent cohorts of patients.
- A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Den Boer ML, Van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JGCAM, Peters TCJM, Van Zutven LJCM, Beverloo HB, Van der Spek PJ, Escherich G, Horstmann MA, Janka-Schaub GE, Kamps WA, Evans WE, Pieters R. Lancet Oncol 10:125-134 (2009). PMID: 19138562 (IF: 14.5) Discovery paper leading to identification of ABL-class and new WHO category in subsequent years.
- Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. Holleman A, Cheok MH, Den Boer ML, Yang W, Veerman AJP, Kazemier KM, Pei P, Cheng C, Pui CH, Relling MV, Janka-Schaub GE, Pieters R and Evans WE. N Eng J Med, 351:533-542 (2004). PMID: 15295046 (IF 38.6) Discovery paper about potential causes of resistance to classical chemotherapeutic drugs.
- Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia. Den Boer ML, Harms DO, Pieters R, Kazemier KM, Göbel U, Körholz D, Graubner U, Haas RJ, Jorch N, Spaar HJ, Kaspers GJL, Kamps WA, Van der Does-van den Berg A, Van Wering ER, Veerman AJP and Janka-Schaub GE. Clin. Oncol. 21, 3262-3268 (2003). PMID: 12947061 (IF 2003 10.9). Seminal paper which resulted into use of these drug response profiles to risk-stratify patients.
The clinical evaluation is reported by Schramm F, Zur Stadt U, Zimmermann M, Jorch N, Pekrun A, Borkhardt A, Imschweiler T, Christiansen H, Faber J, Schmid I, Feuchtinger T, Beron G, den Boer ML, Pieters R, Horstmann MA, Janka-Schaub GE, Escherich G. Results of CoALL 07-03 study childhood ALL based on combined risk assessment by in vivo and in vitro pharmacosensitivity. Blood Adv. 2019 Nov 26;3(22):3688-3699. PMID: 31765480
