Anton W. Langerak, PhD

Langerak-51x53px Associate Professor, Laboratory Medical Immunology,
 Department of Immunology

 Email contact: a.langerak@erasmusmc.nl

 Molecular Immunodiagnostics (MID) Research Group

The research in the MID group is at the interface between normal and malignant lymphoid development. This fundamental knowledge can be translated into better diagnostics, more accurate 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.

One major focus 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 mature leukemias the exact IG and TR composition is thought to 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. 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, followed by multiple additional genetic hits resulting in overt (acute) leukemias or lymphomas. Insight into normal and oncogenic IG-TR recombination events will thus shed light on the pathogenic mechanisms underlying leukemia formation.

Another major focus is on the effect of immune ageing on lymphoid cells (i.e. T cells and also B cells) and the potential relationship with lymphoid malignancies that typically occur in the elderly, such as chronic lymphocytic leukemia (CLL) and large granular lymphocytic (LGL) leukemia.   

fig-1a-circos-360w     

Fig. 1 Circoletto plot highlighting the clonal heterogeneity of CD8+ T-LGL

fig 2b-250 fig 2a-250

 

 

 

 


 

 
Fig. 2 
Increased basal signaling in especially mutated CLL (M-CLL)


Our current research lines are:

  1. T-cell development, TR recombination, and immune ageing (model systems: human thymocytes, Nijmegen breakage syndrome with TR translocus recombinations, immature T-cell leukemias with TR translocations)
  2. Immunopathogenesis of mature lymphoproliferations (model systems: MBL, CLL, T-LGL) with special emphasis on antigenic stimulation, receptor signalling, and genetic aberrations)

Our research is tightly embedded in international networks (EuroClonality, EuroFlow, ERIC) and / or linked with international clinical trials (CLL trials).

 Group members

Anton W. Langerak, Group leader
Jorn Assman, PhD student
Martijn Kolijn, PhD student
Simar Pal Singh, PhD student
Fatemeh Saberi Hosnijeh, Post Doc
Ellen van Gastel-Mol, Research Assistant
Joyce Schilperoord-Vermeulen, Research Assistant
Kim Heezen, Research Assistant
Brigitte van Krimpen, Research Assistant
Tamara Pesic, Research Assistant
Michele van der Klift, Research Assistant
Roxane Wouters, Research Assistant
Barbara Barendregt, Research Assistant 

 Selected Publications

(Check for all publications: Langerak AW in Pubmed)

Kluin PhM, Langerak AW, Beverdam–Vincent J, Geurts-Giele WRR, Visser L, Schuuring E, Van Baarlen J, Lam KH, Seldenrijk K, Kibbelaar RE, De Wit P, Diepstra A, Rosati S, Van Noesel MM, Zwaan CM, Hunting JCB, Hoogendoorn M, Van der Gaag EJ, Van Esser JWJ, De Bont E, Kluin-Nelemans HC, Winter RH, Lo ten Foe JR, Van der Zanden AGM.
Pediatric marginal zone lymphoproliferative disorder of the neck: a Haemophilus influenzae driven immune disorder?
J Pathol. 2015, in press (Epub Feb 26).

Baliakas P, Agathangelidis A, Hadzidimitriou A, Sutton LA, Minga E, Tsanousa A, Scarfò L, Davis Z, Yan XJ, Shanafelt T, Plevova K, Sandberg Y, Vojdeman FJ, Boudjogra M, Tzenou T, Chatzouli M, Chu CC, Veronese S, Gardiner A, Mansouri L, Smedby KE, Bredo Pedersen L, Moreno D, Van Lom K, Giudicelli V, Skuhrova Francova H, Nguyen-Khac F, Panagiotidis P, Juliusson G, Angelis L, Anagnostopoulos A, Lefranc MP, Facco M, Trentin L, Catherwood M, Montillo M, Geisler CH, Langerak AW, Pospisilova S, Chiorazzi N, Oscier D, Jelinek DF, Darzentas N, Belessi C, Davi F, Ghia P, Rosenquist R, Stamatopoulos K.
Not all IGHV3-21 chronic lymphocytic leukemia are equal: prognostic considerations.
Blood. 2015;125:856-859.

Muggen AF, Pillai SY, Kil LP, Van Zelm MC, Van Dongen JJM, Hendriks RW, Langerak A.
Basal Ca2+ signaling is particularly increased in mutated CLL.
Leukemia. 2015;29:321-328.

Baliakas P, Hadzidimitriou A, Sutton LA, Minga E, Agathangelidis A, Tsanousa A, Scarfo L, Davis Z, Yan XJ, Shanafelt T, Plevova K, Sandberg Y, Vojdeman FJ, Boudjogra M, Tzenou T, Chatzouli M, Chu CC, Veronese S, Gardiner A, Mansouri L, Smedby KE, Bredo Pedersen L, Moreno D, Van Lom K, Giudicelli V, Shkurova Francova H, Nguyen-Khac F, Panagiotidis P, Juliusson G, Angelis L, Anagnostopoulos A, Lefranc MP, Trentin L, Catherwood M, Montillo M, Geisler G, Langerak AW, Pospisilova S, Chiorazzi N, Oscier D, Jelinek D, Darzentas N, Belessi C, Davi F, Rosenquist R, Ghia P, Stamatopoulos K.
B-cell receptor stereotypy defined distinct clinical subgroups of CLL: implications for individualizing treatment.
Lancet Hematol. 2014.

Meijers RWJ, Litjens NHR, De Wit EA, Langerak AW, Baan CC, Weimar W, Betjes MGH.
Uremia-associated premature immunological ageing is stably imprinted in the T-cell system and not reversed by kidney transplantation.
Transpl Internat. 2014;27:1272-1284.

Sandberg Y, Kallemeijn MJ, Dik WA, Tielemans D, Wolvers-Tettero ILM, Van Gastel-Mol EJ, Szczepanski T, Pol Y, Darzentas N, Van Dongen JJM, Langerak AW.
Lack of clear TCRA and TCRB clonotypes in CD8+/TCR+ T-cell large granular lymphocyte leukemia: a review on the role of antigenic selection in its immunopathogenesis.
Blood Cancer J. 2014;4:e172.

Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, De la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M.
Obinutuzumab (GA101) plus chlorambucil in patients with CLL and comorbidity.
New Engl J Med. 2014;370:1101-1110.

Larmonie NSD, Van der Spek A, Bogers AJJC, Van Dongen JJM, Langerak AW.
Genetic and epigenetic determinants collectively mediate susceptibility of oncogene breakpoint sites for involvement in ‘Type 1’ and ‘Type 2’ TCR translocations.
Genes Immunity. 2014;15:72-81.

Larmonie NSD, Dik WA, Meijerink JPP, Homminga I, Van Dongen JJM, Langerak AW.
Breakpoint sites disclose the role of the V(D)J recombination machinery in the formation of TCR and non-TCR associated aberrations in human T-ALL.
Haematologica. 2013;98:1173-1184.

Missotten T, Tielemans D, Bromberg JE, Van Hagen PM, Van Lochem EG, Van Dongen JJM, Baarsma GS, Langerak AW.
Multi-color flowcytometric immunophenotyping is a valuable tool for detection of intra-ocular lymphoma in patients presenting with a (pseudo)uveitis.
Ophthalmology. 2013;120:991-996.

Langerak AW, Groenen PJTA, Brüggemann M, Beldjord K, Bellan C, Bonello L, Boone E, Carter I, Catherwood M, Davi F, Delfau-Larue MH, Diss T, Evans PAS, Gameiro P, Garcia Sanz R, Gonzalez D, Grand D, Håkansson A, Hummel M, Liu H, Lombardia L, Macintyre EA, Milner B, Montes-Moreno S, Schuuring E, Spaargaren M, Hodges E, Van Dongen JJM.
EuroClonality / BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations.
Leukemia. 2012;26:2159-2172.

Van Dongen JJM, Lhermitte L, Böttcher S, Almeida J, Van der Velden VHJ, Flores-Montero J, Rawstron A, Asnafi V, Lécrevisse Q, Lucio P, Mejstrikova E, Szczepanski T, Kalina T, De Tute R, Brüggemann M, Sedek L, Cullen M, Langerak AW, Mendonça A, Macintyre E, Martin-Ayuso M, Hrusak O, Vidriales MB, Orfao A.
EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes.
Leukemia. 2012;26:1908-1975.

Agathangelidis A, Darzentas N, Hadzidimitriou A, Brochet X, Murray F, Yan XJ, Davis Z, van Gastel-Mol EJ, Tresoldi C, Chu CC, Cahill N, Giudicelli V, Tichy B, Pedersen LB, Foroni L, Bonello L, Janus A, Smedby K, Anagnostopoulos A, Merle-Beral H, Laoutaris N, Juliusson G, di Celle PF, Pospisilova S, Jurlander J, Geisler C, Tsaftaris A, Lefranc MP, Langerak AW, Oscier DG, Chiorazzi N, Belessi C, Davi F, Rosenquist R, Ghia P, Stamatopoulos K.
Stereotyped B-cell receptors in one third of chronic lymphocytic leukemia: towards a molecular classification with implications for targeted therapeutic interventions.
Blood. 2012;119:4467-4475.

Betjes MGH, Langerak AW, Van der Spek A, De Wit LEA, Litjens NHR.
Excessive premature ageing of circulating T cells in ESRD patients.
Kidney Int. 2011;80:208-217.

Zubakov D, Liu F, Van Zelm MC, Vermeulen J, Oostra BA, Van Duijn CM, Van Dongen JJM, Kayser M, Langerak AW.
Estimating human age from T-cell DNA rearrangements.
Curr Biol. 2010;20:R970-971.