Haemato-Oncology

Prof. dr. R. Delwel, dr. E. de Pater, Prof. dr. M. Raaijmakers, Prof. dr. I.P. Touw, dr. P. Valk,

The research program aims to elucidate key regulatory abnormalities of leukemogenesis. Emphasis of the program is currently on signal transduction derangements and perturbations of transcription and epigenetic control determining functional abnormalities of survival, proliferative, cell cycle, and maturation fates of hematopoietic stem cells.

Another section addresses the role of the interaction between hematopoietic cells and their microenvironment in leukemogenesis. Specific focus is on leukemic progression of leukemia predisposition states, including severe congenital neutropenia, GATA2 deficiency syndrome, Shwachman-Diamond syndrome   and myelodysplastic syndromes.

Finally, the department studies the biology and clinical importance of MRD (measurable residual disease) in Acute Myeloid Leukemia (AML).

Prof. dr. J.J. Cornelissen, dr. E. de Pater

Hematopoietic stem cell transplantation (SCT) is currently an important therapeutic modality for many malignant hematological disorders, as well as its development for gene transfer as a therapeutic modality. Alternative stem cell sources (cord blood) and alternative donors (matched unrelated donors) are increasingly used for hematopoietic stem cell transplantation.

Transplant-related morbidity and mortality of allogeneic SCT is still significant due to acute and chronic graft-versus-host disease (GVHD) and opportunistic infections (mainly reactivations of endogenous herpes viruses).

Our research focuses on:

• The identification and treatment of patients with an impaired immune recovery after transplantation at high risk for specific progressive viral infections.
• The development of alternative approaches to facilitate engraftment and mitigate GVHD
• The development of gene therapeutic approaches for inherited diseases (www.inherinet.org), spin-off acquired diseases, further preclinical development of hematopoietic and mesenchymal stem cell transplantation using gene marked cells.
• The development of innovative hematopoietic stem cell transplantation approaches.

Prof. dr. J.J.M. van Dongen, dr. A.W. Langerak, dr. F.J.T. Staal, dr. V.H.J. van der Velden

This research program focuses on the diagnosis and classification of leukemias and malignant lymphomas as well as on the evaluation of treatment effectiveness during follow-up via detection of low frequencies of malignant cells, i.e. detection of ‚ “minimal residual disease” (MRD). The research program combines molecular and cellular studies on normal and malignant hematopoiesis, particularly focusing on immature lymphoid differentiation. The various types of lymphoid malignancies (leukemias and lymphomas) resemble their normal counterparts. Despite this comparability, the malignant cells exhibit aberrant cellular and genetic characteristics, which can be used for diagnosis, classification, and MRD studies. Thorough insight into normal lymphoid differentiation appears to be highly relevant for translation of new immunobiological information into improved diagnostics. The research program consists of three main projects:

Normal and aberrant V(D)J recombination in leukemias and malignant lymphomas: basic aspects and diagnostic applications

V(D)J recombination of immunoglobulin (Ig) and T-cell receptor (TCR) genes is a key process during early lymphoid differentiation, which is required to establish a broad repertoire of antigen-recognizing receptors. Although the V(D)J recombination process is tightly regulated, aberrant V(D)J recombination occurs, resulting in the coupling of Ig/TCR loci to oncogenes. As a consequence, the involved oncogene is transcriptionally deregulated, eventually resulting in a block in lymphoid differentiation. This differentiation arrest is postulated to lead to a pre-leukemic cell population. Multiple additional genetic hits will result in overt (acute) leukemias or lymphomas.

Insight into normal and oncogenic recombination events will shed light on the pathogenic mechanisms underlying acute leukemia formation. This fundamental knowledge can be translated into better prognostic classification and improved treatment stratification of lymphoid malignancies. As a direct spin-off, these studies might contribute to the identification of novel therapeutic targets.

Immunobiology of acute leukemia and treatment evaluation

Acute leukemia is the most common form of cancer in childhood. Current treatment protocols, consisting of chemotherapy with or without stem cell transplantation can cure the vast majority of patients. However, in 20 to 40% of children the leukemia sooner or later reappears. Apparently, low numbers of leukemic cells, that is ‚”minimal residual disease” (MRD), remain present despite the therapy and finally result in a relapse. How can we detect these low levels of leukemic cells and how can we use MRD information for improving clinical outcome? Over the last couple of years we have developed PCR methods that can detect one leukemic cell amongst up to one million normal cells. Our studies in children with acute lymphoblastic leukemia (ALL) show that such detection of MRD is a very powerful and independent prognostic factor that allows the recognition of patients at high or low risk of relapse.

Our current studies are focused on the development of other sensitive methods for MRD detection, particularly flow cytometric immunophenotyping, and on the evaluation of the clinical significance of MRD in children with acute myeloid leukemia, infants with ALL, and in specific genetic subgroups of childhood ALL. The aims of these studies are to improve MRD monitoring and to establish its clinical significance, thereby allowing patient-tailored therapy of children with leukemia. Such patient-tailored therapy will hopefully result in an improved clinical outcome in children at high risk for relapse and in less intense therapy, and thereby less side effects, in children with a very low risk of relapse.

Gene expression profiles in immature lymphoid cells and acute lymphoblastic leukemias

Gene expression profiles determine the differentiation lineage, developmental stage, and activation stage of the involved cells. Just like in any other cell type, regulation of gene expression in lymphocytes is largely controlled at the level of transcription initiation by transcription factors and transcriptional repressors. The study focuses on transcription factors and signaling routes that are controlling the most immature steps of lymphoid differentiation. In parallel, the abnormal regulation of gene expression in acute lymphoblastic leukemias is studied and compared to corresponding normal immature T and B cell subpopulations. Results of these comparative studies are being exploited for developing new diagnostic tools.

Prof. dr. H.G.P. Raaijmakers, Prof. dr. J.J. Cornelissen, Prof. dr. R. Delwel, Prof. dr. B. Löwenberg, dr. M. Jongen, dr. B. Wouters, Prof. dr. P. Sonneveld, dr. P.J.M. Valk, dr. E. de Pater

Within this theme we link the identification of molecular mechanisms in the development of hematopoietic neoplasms, by applying state-of-the-art technologies, to diagnostics, prognostics and therapeutics. We evaluate and implement clinical investigational drugs and procedures.

Key-issues of this theme are:

• Large international clinical trials and correlative lab investigations
• Prognostic factors and clinical decision-making
• Impact of genetic studies on diagnosis, prognosis and treatment
• Molecular therapeutics (e.g., ATRA treatment of APL, imatinib treatment in CML, FLT3 and IDH inhibitors for AML and various treatment modalities for MM)
• Ethical issues in clinical trials

Early implementation of potential active oncolytic agents (small molecules) in a controlled clinical trial setting of Phase I/II trials, designed for designated targets in hemato-oncology diseases:

A Clinical Trial Unit (CTU) for this specific goal is operative. Through this unit we have been able to get access to promising ”pipe-line” products from international development programs of several pharmaceutical companies to test in our programs for these diseases. The department has established a leading role in initiating and conducting pivotal clinical studies with new agents in local phase I/II trials and national phase II/III clinical trials with targeted therapies.

Development of allogeneic stem cell transplantation into a widely applicable modality of immunotherapy of leukemia, lymphoma and related diseases:

This part of the program has been built on a 20-year experience of allogeneic and autologous stem cell transplantation. It has transformed from an experimental treatment modality into a well-structured program that focuses on ’graft vs leukemia’ as a means to control and eradicate Minimal Residual Disease (MRD). The program has developed special interest and background in immune reconstitution after stem cell transplantation and ‘Reduced Intensity Conditioning’(RIC) as a non-toxic approach to immunotherapy. More recently this program has been extended towards the development and application of CAR-T cell therapies.

National and international conducted phase III trials on critical questions in hemato-oncology diseases:

The department of Hematology has an initiating and leading position in the (inter)national HOVON-SAKK trial group (www.hovon.nl). The clinical trials conducted by HOVON include the treatment of various hematologic malignancies and asses the additive effects of novel treatment modalities. Many HOVON trials have been conducted together with parallel collection of and biological studies on tumour samples. The activities in this field reflect the focus on translational medicine, which has been defined as one of the most important challenges for clinical research in the department. An extensive data and tissue bank of various hematologic malignancies has been generated. This source is now being used for large-scale genomic analysis for disease-related risk analysis, based on high-throughput techniques, such as next generation sequencing. The specimens collected in the clinical trials are studied in detail on various molecular levels (DNA, RNA, histone and DNA methylation, etc.), at the start of treatment and during the course of disease (MRD detection), to reveal novel biomarkers with the aim to improve precision medicine of patients with hematologic malignancies.