Group leader: Dr. Mirjam Belderbos
Hematopoietic stem cells
Hematopoietic stem cells (HSCs) are responsible for the production of all mature blood cell types throughout life, generating billions of mature blood cells each day. Aside from their role in homeostatic hematopoiesis, HSCs are crucial to regenerate the hematopoietic system upon myeloablative challenge, such as chemotherapy or transplantation.
Hematopoietic stem cell lineage tracing: from mice to humans
To understand how a relatively small number of HSCs (re-)generate the entire hematopoietic system, our group integrates state-of-the-art single cell methods with clinical data and primary patient samples. Using DNA barcodes to mark individual HSCs and to trace their clonal ancestry in vivo (Belderbos et al, Blood 2017; Methods Mol Biol 2019), we have recently demonstrated that only a small fraction of human umbilical cord blood CD34+ cells generate offspring in murine xenografts (Belderbos et al, Biol Blood Marrow Transpl 2020). Importantly, the frequency of clonogenic cells differed up to 10-fold between umbilical cord blood donors, which may have important consequences for the selection of umbilical cord blood donors for HSC transplantation (HSCT). Inspired to translate these findings to human HSCT recipients, in collaboration with the group of Ruben van Boxtel, we have adopted a novel lineage tracing method, using naturally occurring somatic mutations as “barcodes” to identify and trace individual HSCs in humans. Using this approach in blood and bone marrow of human HSCT recipients and their donors, we found that HSCT does not cause stem cell mutations in the majority of cases.
Long-term integrity of hematopoiesis in stem cell transplantation survivors
HSCT is the first and most commonly applied type of stem cell therapy in humans. Every year, over 40.000 patients undergo HSCT, as a curative therapy for various diseases, including high-risk leukemia. Due to improved treatment protocols, the number of HSCT survivors and their life expectancy continue to increase. It is yet unknown how tranplanted HSCs maintain their life-long integrity. To address this question, our lab leads an ongoing clinical/translational trial in long-term HSCT survivors. By integrating clinical data and molecular features of hematopoiesis in these patients, we aim to define critical determinants that guide HSC longevity after HSCT, which might be targeted therapeutically.
Origins of pediatric bone marrow failure and myelodysplasia
Our group also focuses on the origins and mechanisms of HSC dysfunction in pediatric bone marrow failure. Using single-cell sequencing strategies, we aim to define which hematopoietic cell populations are involved in the pathogenesis of bone marrow failure and myelodysplasia, and characterize the genomic pathways active within these cells. Ultimately, we envision that this will contribute to novel strategies to predict the occurrence of bone marrow failure/myelodysplasia, allowing for targeted intervention and preventive measures.
2. KIR3DS1 directs NK-cell-mediated protection against human adenovirus infections. Science Immunol. 2021;6(63):eabe2942.
3. Jacobs S, Ausema A, Zwart E, Weersing E, Kingma MJ, El Menshawi YAS, de Haan G, Bystrykh LV, Belderbos ME: Quantitative distribution of patient-derived leukemia clones in murine xenografts revealed by cellular barcodes. Leukemia 2020;34(6):1669-1674.
4. Belderbos ME, Gennery AR, Dvorak CC, Blok HJ, Eikema DJ, Silva JMF, Veys P, Neven B, Buckley R, Cole T, Cowan MJ, Goebel WS, Hoenig M, Kuo CY, Stiehm ER, Wynn R, Bierings M; Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation and the Primary Immune Deficiency Treatment Consortium: Outcome of domino hematopoietic stem cell transplantation in human subjects: An international case series. J Allergy Clin Immunol. 2018 Nov;142(5):1628-1631.e4.
5. Belderbos ME, Koster T, Ausema B, Jacobs S, Sowdagar S, Zwart E, de Bont E, de Haan G, Bystrykh LV.: Clonal selection and asymmetric distribution of human leukemia in murine xenografts revealed by cellular barcoding. Blood. 2017 Jun 15;129(24):3210-3220.
Our group consists of a multidisciplinary team, with fundamental biologists as well as clinical researchers. The group is led by dr. Mirjam Belderbos, MD, PhD. Next to her scientific activities, dr. Belderbos works as a pediatric oncologist in hematopoietic stem cell transplantation. Core values in our group are collaboration, curiosity and clinical impact.