Molecular Immunodiagnostics (MID) Research Group
Focus of the research in the MID research group has always been on the interface between normal, dysregulated and malignant lymphoid development. One major aspect of our work is around V(D)J recombination of immunoglobulin (IG) and T-cell receptor (TR) genes, which is a key process during (early) lymphoid differentiation to establish a broad repertoire of antigen-recognizing receptors. In (chronic) lymphoid malignancies the exact IG and TR composition is thought to -at least partly- reflect antigenic stimulation, which may play a role in pathogenesis. Although the V(D)J recombination process is tightly regulated, aberrant V(D)J recombination occurs, resulting in the coupling of IG-TR loci to oncogenes that are transcriptionally deregulated, eventually resulting in a block in lymphoid differentiation. Insight into IG-TR recombination events will thus shed light on the pathogenic mechanisms underlying leukemia formation. Another major aspect of our research is on immune ageing of lymphoid cells (both T and B cells) and the potential relationship with lymphoid malignancies in elderly, such as chronic lymphocytic leukemia (CLL) and large granular lymphocytic (LGL) leukemia.
Fundamental knowledge on biological aspects of lymphoid cells under various conditions can be translated into better diagnostics, more accurate prognostic classification, and improved treatment stratification of (chronic) lymphoid malignancies. Also, these studies will pave the way for sensitive (immune)monitoring and might contribute to the identification of novel therapeutic targets for these diseases.
Current research lines in the MID research group:
- Prognostic biomarkers and minimal disease monitoring for personalized treatment in CLL
CLL is a clinically heterogeneous disease, which is divided into prognostically relevant subgroups based on the mutation status of the IGHV genes encoding the B-cell receptor (BCR) and/or quasi-identical (stereotypic) BCR. Together with international partners, we will be further dissecting these immunogenetic subsets to identify underlying biological mechanisms, and potential biomarkers and therapy targets. With the advent of new CLL treatment options that lead to deeper and longer remissions and eventually may result in cure, the need for sensitive monitoring of minimal residual disease (MRD) has become more and more important. Technological breakthroughs in multi-parameter flow cytometry and molecular methodology (NGS, qPCR, ddPCR) allow further optimization of these strategies in European networks with leading roles for our group.
- Dissecting immune dysregulation and aberrations in T-LGL leukemia
T-LGL leukemia is a relatively rare and indolent disease, which can present with features of associated (auto)immune dysregulation, which we have studied for a long time. Recently, together with partners, we have initiated a novel national LGL registry and biobank (IDeAL, Immune Dysregulation & Aberrations in LGL leukemia). This cohort will allow us to get a more comprehensive understanding of the clinical heterogeneity and biological characteristics in order to find (common) mechanisms of LGL leukemogenesis and LGL-associated immune dysregulation.
- Early detection of leukemia / lymphoma in populations at risk
Particular groups of individuals (immunodeficient patients, transplant patients under immune suppression, individuals with a family history of leukemia / lymphoma) are at risk of lymphoproliferative disease. Early detection of leukemia / lymphoma is the focus of a project embedded in an EU consortium called NOVEL, which aims to define common, underlying molecular mechanisms of leukemogenesis and to find (immunological) biomarkers
The above MID research lines are tightly embedded in national (Chronic Leukemia Research Center, HOVON CLL working group) and international (EuroClonality, EuroFlow, ERIC) networks and / or linked with (inter)national clinical trials.
Figure 1 – Continuum of IG / TR repertoire diversity, ranging from polyclonal to monoclonal (A). Diversity is detectable with low-throughput methods (B) but the resolution of high-throughput sequencing technology (C) is much higher. Figure published in J Immunol 2017;198:3765.
Figure 2 – Heatmap analysis showing clear correlation between transcriptomes of TCRγδ+ T-LGL, and lower correlation to healthy control TCRγδ+ T cell subset transcriptomes. Figure published in PlosOne 2017; 12: e0175670.
- Anton W. Langerak, Principal investigator
- Jorn Assman, PhD student
- Martijn Kolijn, PhD student
- Paul Hengeveld, PhD student (from Sep 2019)
- Simar Pal Singh, PhD student
- Alice F. Muggen, PhD student
- Fatemeh Saberi Hosnijeh, Post Doc
- Ellen van Gastel-Mol, technician
- Joyce Schilperoord-Vermeulen, technician
- Kim Heezen, technician
- Michèle van der Klift, technician
- Roxane Wouters, technician
- Brigitte van Krimpen, technician/quality officer
- Barbara Barendregt, technician/project coordination
Former group members
- Willem A Dik, PhD (postdoc)
- Ruud WJ Meijers, PhD (postdoc)
- Mirjam van der Burg, PhD (PhDstudent)
- Yorick Sandberg, MD, PhD (PhDstudent)
- Nicole S Larmonie. PhD (PhDstudent)
- Martine J Kallemeijn, PhD (PhDstudent)
- Ingrid LM Wolvers-Tettero, technician
- Patrick Boor, technician
- Wietske Harts, technician
- Monique Oud, technician
- Brenda Verhaaf, technician
- Jos de Vos, technician
- Dennis Tielemans, technician
- Bob van Turnhout, technician
- Ashley van der Spek, technician
- Tamara Wabeke, technician
- Irene Groen-van Mourik, technician
- Tamara Pesic, technician
(Check for all publications: Langerak AW in Pubmed)
- Kallemeijn MJ. De Ridder D, Schilperoord – Vermeulen J, van der Klift MY, Sandberg Y, Van Dongen JJM, Langerak AW. Dysregulated signaling, proliferation and apoptosis impact on the pathogenesis of TCRγδ+ T cell large granular lymphocyte lymphoproliferations. PLOS One 2017;12: e0175670
- Langerak AW, Brüggemann M, Davi F, Darzentas N, Gonzalez D, Cazzaniga G, Giudicelli V, Lefranc MP, Giraud M, Macintyre EA, Hummel M, Pott C, Groenen PJTA, Stamatopoulos K – on behalf of the EuroClonality–NGS consortium. High-throughput immunogenetics for clinical and research applications in immuno-hematology: potential and challenges. J Immunol 2017;198:3765-3774
- Rosenquist R, Ghia P, Hadzidimitriou A, Sutton LA, Agathangelidis A, Baliakas P, Darzentas N, Giudicelli V, Lefranc MP, Langerak AW, Belessi C, Davi F, Stamatopoulos K, on behalf of ERIC, the European Research Initiative on CLL. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations. Leukemia 2017;31:1477-1481
- Kallemeijn MJ, Van der Klift MY, Brouwer E, Boots AMH, Abdulahad WH, Verhaar JAN, Van Dongen JJM, Langerak AW. Ageing and latent CMV infection impact maturation, differentiation and exhaustion profiles of T-cell receptor gammadelta T-cells. Sci Rep 2017;7:5509-5516
- Dimier N, Delmar P, Ward C, Morariu-Zamfir R, Fingerle-Rowson G, Bahlo J, Fischer K, Eichhorst B, Goede V, Van Dongen JJM, Ritgen M, Böttcher S, Langerak AW, Kneba M, Hallek M. A model for predicting effect of treatment on progression-free survival using MRD as a surrogate endpoint in CLL. Blood 2018:131:955-962
- Baliakas P, Mattsson M, Hadzidimitriou A, Minga E, Agathangelidis A, Sutton LA, Scarfo L, Davis Z, Yan XJ, Plevova K, Sandberg Y, Vojdeman FJ, Tzenou T, Chu CC, Veronese S, Mansouri L, Smedby KE, Giudicelli V, Nguyen-Khac F, Panagiotidis P, Juliusson G, Anagnostopoulos A, Lefranc MP, Trentin L, Catherwood M, Montillo M, Niemann CU, Langerak AW, Pospisilova S, Stavroyianni N, Chiorazzi N, Oscier D, Jelinek DF, Shanafelt T, Darzentas N, Belessi C, Davi F, Ghia P, Rosenquist R, Stamatopoulos K. No benefit from advances in chemoimmunotherapy for chronic lymphocytic leukemia patients belonging to stereotyped subsets #1 and #2. Haematologica 2018;103:e158-e161
- Langerak AW, Assmann JLJC. LGL cells and immune dysregulation diseases – the chicken or the egg. Haematologica 2018;103:193-194
- Kallemeijn MJ, Kavelaars FG, Van der Klift MY, Wolvers-Tettero ILM, Valk PJM, Van Dongen JJM, Langerak AW. Next-generation sequencing analysis of the human TCRγδ+ T-cell repertoire reveals shifts in Vγ and Vδ usage in memory cells upon aging. Front Immunol 2018;9:448
- Pal Singh S, de Bruijn MJW, de Almeida MP, Meijers RWJ, Nitschke L, Langerak AW, Pillai SY, Stadhouders R, Hendriks RW. Identification of distinct unmutated chronic lymphocytic leukemia subsets in mice based on their T cell dependency. Front Immunol 2018;9:1996
- Langerak AW, Ritgen M, Goede V, Robrecht S, Bahlo J, Fischer K, Steurer M, Trněný M, Mulligan SP, Mey UJM, Trunzer K, Fingerle-Rowson G, Humphrey K, Stilgenbauer S, Böttcher S, Brüggemann M, Hallek M, Kneba M, Van Dongen JJM. Prognostic value of MRD in CLL patients with comorbidities receiving chlorambucil plus obinutuzumab or rituximab. Blood 2019;133:494-497
- Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. A Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory CLL Eradicates Minimal Residual Disease and Prolongs Survival: Long-Term Outcomes of the MURANO Phase 3 Study. J Clin Oncol 2019;37:269-277
- De Hoog J, Dik WA, Lu L, Heezen KC, Ten Berge JCEM, Swagemakers SMA, Van der Spek PJ, Van Dongen JJM, Van der Velden VHJ, Rothova A, Langerak AW. Combined cellular and soluble mediator analysis for improved diagnosis of vitreoretinal lymphoma. Acta Ophthalmol, 2019 (Epub Jan 27).
- Meijers RWJ, Muggen AF, Leon LG, De Bie M, Van Dongen JJM, Hendriks RW, Langerak AW. Responsiveness of CLL cells to B cell receptor stimulation is associated with low expression of regulatory molecules of the NF-kB pathway. Haematologica 2019 (Epub May 16)
- Brüggemann B, Kotrová M, Knecht H, Bartram J, Boudjogrha M, Bystry V, Fazio G, Froňková E, Giraud M, Grioni A, Hancock J, Herrmann D, Jiménez C, Krejci A, Moppett J, Reigl T, Salson M, Scheijen B, Schwarz M, Songia S, Svaton M, Van Dongen JJM, Villarese P, Wakeman S, Wright G, Cazzaniga G, Davi F, García-Sanz R, Gonzalez D, Groenen PJTA, Hummel M, Macintyre EA, Stamatopoulos K, Pott C, Trka J, Darzentas N, Langerak AW, on behalf of the EuroClonality-NGS working group. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukemia; a EuroClonality-NGS validation study. Leukemia 2019, in press.
- Knecht H, Reigl T, Kotrová M, Appelt F, Stewart P, Bystry V, Krejci A, Grioni A, Pal K, Stranska K, Plevova K, Rijntjes J, Songia S, Svatoň M, Froňková E, Bartram J, Scheijen B, Herrmann D, García-Sanz R, Hancock J, Moppett J, Van Dongen JJM, Cazzaniga G, Davi F, Groenen PJTA, Hummel M, Macintyre EA, Stamatopoulos K, Trka J, Langerak AW, Gonzalez D, Pott C, Brüggemann M, Darzentas N; EuroClonality-NGS Working Group. Quality control and quantification in IG/TR next-generation sequencing marker identification: protocols and bioinformatic functionalities by EuroClonality-NGS. Leukemia 2019 (Epub June 22)
- Scheijen B, Meijers RWJ, Rijntjes J, van der Klift MY, Möbs M, Steinhilber J, Reigl T, van den Brand M, Kotrová M, Ritter JM, Catherwood MA, Stamatopoulos K, Brüggemann M, Davi F, Darzentas N, Pott C, Fend F, Hummel M, Langerak AW, Groenen PJTA; EuroClonality-NGS Working Group. Next-generation sequencing of immunoglobulin gene rearrangements for clonality assessment: a technical feasibility study by EuroClonality-NGS. Leukemia 2019 (Epub June 13).