Target and therapy discovery in lymphoma and multiple myeloma

Research aims

Our research is focused on the molecular and cellular aspects of the pathogenesis of (mature) B-cell malignancies, including non-Hodgkin lymphoma, specifically diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and Waldenström's Macroglobulinaemia (WM). Major aims are (1) to identify and molecularly dissect the signaling pathways involved in the pathogenesis of mature B-cell malignancies, (2) to explore and exploit microenvironment-dependence as their Achilles’ heel, and (3) to identify novel therapeutic targets, to overcome therapy resistance and improve treatment of patients.

Marcel Spaargaren

Dr. Marcel Spaargaren

Favorite molecules

More specifically, regarding these aims, we explore(d) and exploit the molecular and functional oncogenic aspects of signalling by the B-cell antigen receptor (BCR), Toll-like receptors (through MYD88/IRAK), chemokines (e.g. CXCL12/CXCR4), receptor tyrosine kinases (e.g., HGF/MET) and WNTs, and the role of heparan sulfate proteoglycans (i.e., CD44 and Syndecan-1), transcription factors (e.g., FOXP1 and NFκB), adhesion molecules (integrins and cadherins), kinases (e.g., BTK, PI3K and HCK) and apoptosis-regulatory Bcl-2 family proteins (e.g., BCL-2 and MCL-1).

Tumor microenvironment

One of our long-standing research interests involves the molecular and functional aspects of integrin-mediated cell adhesion and migration. Our studies on the mechanism underlying the unprecedented clinical efficacy of the Bruton’s tyrosine kinase (BTK) inhibitor Ibrutinib have established induction of ‘homelessness’, by targeting the lymphoid organ retention and homing of the malignant cells, thereby exploiting their microenvironment-dependence, as a powerful therapeutic strategy for treatment of CLL, MCL and WM. Unfortunately, however, a significant subset of patients is resistant or will acquire resistance to current treatments (including ibrutinib); hence, there is still a high need for development of novel therapies.

Target and therapy discovery

Currently, our main focus is on target- and drug-discovery and preclinical development of targeted (combination-)therapy. This includes unbiased functional genomic CRISPR-Cas9 library knockout screens, e.g., loss-of-adhesion screens for BCR- and chemokine-controlled integrin-mediated adhesion and drug sensitizer screens for the BCL-2 inhibitor venetoclax, in order to identify novel therapeutic targets and (combinations of) drugs to overcome therapy resistance and improve treatment of patients with B-cell malignancies.

Collaborations

Within LYMMCARE (Lymphoma and Multiple Myeloma Center Amsterdam), a center of expertise for mature B-cell malignancies of the Depts. of Pathology, Hematology and Experimental Immunology, we have a close and fruitful collaboration with Jeroen Guikema, Marie Jose Kersten, Richard Groen, Maria Themeli, Tuna Mutis and Sonja Zweegman for our studies on MM and WM, and with Eric Eldering and Arnon Kater for our studies on MCL and CLL, as nicely illustrated by this ‘research highlight’ on the website of the CCA: Major breakthroughs in lymphoma and leukemia therapy: Ibrutinib and Venetoclax

News articles on the CCA website

Identification of a novel therapeutic target for treatment of mantle cell lymphoma
A prominent role for the chemokine CXCL12γ in multiple myeloma

Group members

  • Martin de Rooij, PhD
  • Sander Joosten, PhD
  • Annemieke Kuil, research technician
  • Fangxue Ma, PhD candidate
  • Britt van der Swaan, PhD candidate
  • Liu Yang, PhD candidate
  • Simon Mobach, PhD candidate (co-supervised with Martine Smit and Arnon Kater)
  • Steven Pals, professor emeritus

    Key publications

    All publications of the Spaargaren group can be viewed here: Pubmed

    Selected publications as of 2021:

    The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma.
    Lantermans HC, Ma F, Kuil A, van Kesteren S, Yasinoglu S, Yang G, Buhrlage SJ, Wang J, Gray NS, Kersten MJ, Treon SP, Pals ST,Spaargaren M.
    Leukemia. 2024 Jul;38(7):1570-1580.

    What's brewing for MALT1 in lymphoma?
    Spaargaren M.
    Blood. 2023 Dec 7;142(23):1939-1941.

    The oncogenic human B-cell lymphoma MYD88 L265P mutation genocopies activation by phosphorylation at the Toll/interleukin-1 receptor (TIR) domain.
    Minderman M, Lantermans H, van der Zwaan C, Hoogendijk AJ, van den Biggelaar M, Kersten MJ,Spaargaren M*, Pals ST*.
    Blood Cancer J. 2023 Aug 18;13(1):125.

    MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas.
    Minderman M, Lantermans HC, Grüneberg LJ, Cillessen SAGM, Bende RJ, van Noesel CJM, Kersten MJ, Pals ST,Spaargaren M.
    Blood Cancer J. 2023 Mar 15;13(1):37.

    Inhibition of casein kinase 2 sensitizes mantle cell lymphoma to venetoclax through MCL-1 downregulation.
    Thus YJ, De Rooij MFM, Swier N, Beijersbergen RL, Guikema JEJ, Kersten MJ, Eldering E, Pals ST, Kater AP,Spaargaren M.
    Haematologica. 2023 Mar 1;108(3):797-810.

    Tipping the balance: toward rational combination therapies to overcome venetoclax resistance in mantle cell lymphoma.
    Thus YJ, Eldering E, Kater AP,Spaargaren M.
    Leukemia. 2022 Sep;36(9):2165-2176.

    A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways.
    de Rooij MFM, Thus YJ, Swier N, Beijersbergen RL, Pals ST,Spaargaren M.
    Nat Commun. 2022 Apr 19;13(1):2136.

    Immune evasion in primary testicular and central nervous system lymphomas: HLA loss rather than 9p24.1/PD-L1/PD-L2 alterations.
    Minderman M, Amir A, Kraan W, Schilder-Tol EJM, Oud MECM, Scheepstra CG, Noorduyn AL, Kluin PM, Kersten MJ,Spaargaren M*, Pals ST*.
    Blood. 2021 Sep 30;138(13):1194-1197.

    Syndecan-1 and stromal heparan sulfate proteoglycans: key moderators of plasma cell biology and myeloma pathogenesis.
    Ren Z,Spaargaren M, Pals ST.
    Blood. 2021 Apr 1;137(13):1713-1718.

    Identification of the SRC-family tyrosine kinase HCK as a therapeutic target in mantle cell lymphoma.
    Lantermans HC, Minderman M, Kuil A, Kersten MJ, Pals ST,Spaargaren M.
    Leukemia. 2021 Mar;35(3):881-886.

    The CXCL12gamma chemokine immobilized by heparan sulfate on stromal niche cells controls adhesion and mediates drug resistance in multiple myeloma.
    Ren Z, Lantermans H, Kuil A, Kraan W, Arenzana-Seisdedos F, Kersten MJ,Spaargaren M*, Pals ST*.
    J Hematol Oncol. 2021 Jan 12;14(1):11.

    Selected publications before 2020:

    MET Signaling Overcomes Epidermal Growth Factor Receptor Inhibition in Normal and Colorectal Cancer Stem Cells Causing Drug Resistance.
    Joosten SPJ, Mizutani T,Spaargaren M, Clevers H, Pals ST.
    Gastroenterology. 2019 Oct;157(4):1153-1155.e1.

    Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options.
    van Andel H, Kocemba KA,Spaargaren M*, Pals ST*.
    Leukemia. 2019 May;33(5):1063-1075.

    Syndecan-1 promotes Wnt/β-catenin signaling in multiple myeloma by presenting Wnts and R-spondins.
    Ren Z, van Andel H, de Lau W, Hartholt RB, Maurice MM, Clevers H, Kersten MJ,Spaargaren M*, Pals ST*.
    Blood. 2018 Mar 1;131(9):982-994.

    MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms.
    Joosten SPJ, Zeilstra J, van Andel H, Mijnals RC, Zaunbrecher J, Duivenvoorden AAM, van de Wetering M, Clevers H,Spaargaren M*, Pals ST*.
    Gastroenterology. 2017 Oct;153(4):1040-1053.e4.

    Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease.
    van Andel H, Kocemba KA, de Haan-Kramer A, Mellink CH, Piwowar M, Broijl A, van Duin M, Sonneveld P, Maurice MM, Kersten MJ,Spaargaren M*, Pals ST*.
    Oncogene. 2017 Apr;36(15):2105-2115.

    The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells.
    van Keimpema M, Grüneberg LJ, Schilder-Tol EJ, Oud ME, Beuling EA, Hensbergen PJ, de Jong J, Pals ST,Spaargaren M.
    Haematologica. 2017 Mar;102(3):573-583.

    Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins.
    van Andel H, Ren Z, Koopmans I, Joosten SP, Kocemba KA, de Lau W, Kersten MJ, de Bruin AM, Guikema JE, Clevers H,Spaargaren M*, Pals ST*.
    Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):376-381.

    Ibrutinib and idelalisib target B cell receptor- but not CXCL12/CXCR4-controlled integrin-mediated adhesion in Waldenström macroglobulinemia.
    de Rooij MF, Kuil A, Kraan W, Kersten MJ, Treon SP, Pals ST,Spaargaren M.
    Haematologica. 2016 Mar;101(3):e111-5.

    The forkhead transcription factor FOXP1 represses human plasma cell differentiation.
    van Keimpema M, Grüneberg LJ, Mokry M, van Boxtel R, van Zelm MC, Coffer P, Pals ST,Spaargaren M.
    Blood. 2015 Oct 29;126(18):2098-109.

    BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future.
    Spaargaren M, de Rooij MF, Kater AP, Eldering E.
    Oncogene. 2015 May 7;34(19):2426-36.

    Ibrutinib for AML? Check CD117 (KIT)!
    Spaargaren M.
    Lancet Haematol. 2015 May;2(5):e180-1.

    Ibrutinib and idelalisib synergistically target BCR-controlled adhesion in MCL and CLL: a rationale for combination therapy.
    de Rooij MF, Kuil A, Kater AP, Kersten MJ, Pals ST,Spaargaren M.
    Blood. 2015 Apr 2;125(14):2306-9.

    Diffuse large B cell lymphomas relapsing in the CNS lack oncogenic MYD88 and CD79B mutations.
    Kersten MJ, Kraan W, Doorduijn J, Bromberg J, Lam K, Kluin PM, van der Holt BJ,Spaargaren M*, Pals ST*.
    Blood Cancer J. 2014 Dec 12;4(12):e266.

    FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells.
    van Keimpema M, Grüneberg LJ, Mokry M, van Boxtel R, Koster J, Coffer PJ, Pals ST,Spaargaren M.
    Blood. 2014 Nov 27;124(23):3431-40.

    High prevalence of oncogenic MYD88 and CD79B mutations in primary testicular diffuse large B-cell lymphoma.
    Kraan W, van Keimpema M, Horlings HM, Schilder-Tol EJ, Oud ME, Noorduyn LA, Kluin PM, Kersten MJ,Spaargaren M*, Pals ST*.
    Leukemia. 2014 Mar;28(3):719-20.

    Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling.
    Zeilstra J, Joosten SP, van Andel H, Tolg C, Berns A, Snoek M, van de Wetering M,Spaargaren M, Clevers H, Pals ST.
    Oncogene. 2014 Jan 30;33(5):665-70.

    High prevalence of oncogenic MYD88 and CD79B mutations in diffuse large B-cell lymphomas presenting at immune-privileged sites.
    Kraan W, Horlings HM, van Keimpema M, Schilder-Tol EJ, Oud ME, Scheepstra C, Kluin PM, Kersten MJ,Spaargaren M*, Pals ST*.
    Blood Cancer J. 2013 Sep 6;3(9):e139.

    The hypoxia target adrenomedullin is aberrantly expressed in multiple myeloma and promotes angiogenesis.
    Kocemba KA, van Andel H, de Haan-Kramer A, Mahtouk K, Versteeg R, Kersten MJ,Spaargaren M*, Pals ST*.
    Leukemia. 2013 Aug;27(8):1729-37.

    The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia.
    de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST,Spaargaren M.
    Blood. 2012 Mar 15;119(11):2590-4.

    Transcriptional silencing of the Wnt-antagonist DKK1 by promoter methylation is associated with enhanced Wnt signaling in advanced multiple myeloma.
    Kocemba KA, Groen RW, van Andel H, Kersten MJ, Mahtouk K,Spaargaren M*, Pals ST*.
    PLoS One. 2012;7(2):e30359.

    Lymphoma spread? Target CD47-SIRPα!
    Spaargaren M.
    Blood. 2011 Nov 3;118(18):4762-4.

    N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation.
    Groen RW, de Rooij MF, Kocemba KA, Reijmers RM, de Haan-Kramer A, Overdijk MB, Aalders L, Rozemuller H, Martens AC, Bergsagel PL, Kersten MJ, Pals ST,Spaargaren M.
    Haematologica. 2011 Nov;96(11):1653-61.

    Disruption of heparan sulfate proteoglycan conformation perturbs B-cell maturation and APRIL-mediated plasma cell survival.
    Reijmers RM, Groen RW, Kuil A, Weijer K, Kimberley FC, Medema JP, van Kuppevelt TH, Li JP,Spaargaren M*, Pals ST*.
    Blood. 2011 Jun 9;117(23):6162-71.

    Targeting EXT1 reveals a crucial role for heparan sulfate in the growth of multiple myeloma.
    Reijmers RM, Groen RW, Rozemuller H, Kuil A, de Haan-Kramer A, Csikós T, Martens AC,Spaargaren M*, Pals ST*.
    Blood. 2010 Jan 21;115(3):601-4.

    Illegitimate WNT pathway activation by beta-catenin mutation or autocrine stimulation in T-cell malignancies.
    Groen RW, Oud ME, Schilder-Tol EJ, Overdijk MB, ten Berge D, Nusse R,Spaargaren M*, Pals ST*.
    Cancer Res. 2008 Sep 1;68(17):6969-77.

    Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis.
    Zeilstra J, Joosten SP, Dokter M, Verwiel E, Spaargaren M, Pals ST.
    Cancer Res. 2008 May 15;68(10):3655-61.

    The small GTPase Ral mediates SDF-1-induced migration of B cells and multiple myeloma cells.
    de Gorter DJ, Reijmers RM, Beuling EA, Naber HP, Kuil A, Kersten MJ, Pals ST,Spaargaren M.
    Blood. 2008 Apr 1;111(7):3364-72.

    Lymphoma dissemination: the other face of lymphocyte homing.
    Pals ST, de Gorter DJ,Spaargaren M.
    Blood. 2007 Nov 1;110(9):3102-11.

    The B cell antigen receptor controls AP-1 and NFAT activity through Ras-mediated activation of Ral.
    de Gorter DJ, Vos JC, Pals ST,Spaargaren M.
    J Immunol. 2007 Feb 1;178(3):1405-14.

    Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing.
    de Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, van Gils JM, Hendriks RW, Pals ST,Spaargaren M.
    Immunity. 2007 Jan;26(1):93-104.

    Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma.
    Tjin EP, Groen RW, Vogelzang I, Derksen PW, Klok MD, Meijer HP, van Eeden S, Pals ST,Spaargaren M.
    Blood. 2006 Jan 15;107(2):760-8.

    Follicular dendritic cells catalyze hepatocyte growth factor (HGF) activation in the germinal center microenvironment by secreting the serine protease HGF activator.
    Tjin EP, Bende RJ, Derksen PW, van Huijstee AP, Kataoka H,Spaargaren M*, Pals ST*.
    J Immunol. 2005 Sep 1;175(5):2807-13.

    Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by secreting the serine protease HGF-activator.
    Tjin EP, Derksen PW, Kataoka H,Spaargaren M*, Pals ST*.
    Blood. 2004 Oct 1;104(7):2172-5.

    Illegitimate WNT signaling promotes proliferation of multiple myeloma cells.
    Derksen PW, Tjin E, Meijer HP, Klok MD, MacGillavry HD, van Oers MH, Lokhorst HM, Bloem AC, Clevers H, Nusse R, van der Neut R,Spaargaren M*, Pals ST*.
    Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6122-7.

    The B cell antigen receptor controls integrin activity through Btk and PLCgamma2.
    Spaargaren M, Beuling EA, Rurup ML, Meijer HP, Klok MD, Middendorp S, Hendriks RW, Pals ST.
    J Exp Med. 2003 Nov 17;198(10):1539-50.

    The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma.
    Derksen PW, de Gorter DJ, Meijer HP, Bende RJ, van Dijk M, Lokhorst HM, Bloem AC,Spaargaren M, Pals ST.
    Leukemia. 2003 Apr;17(4):764-74.

    Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma.
    Derksen PW, Keehnen RM, Evers LM, van Oers MH,Spaargaren M, Pals ST.
    Blood. 2002 Feb 15;99(4):1405-10.

    Regulation of cytokine signaling by B cell antigen receptor and CD40-controlled expression of heparan sulfate proteoglycans.
    van der Voort R, Keehnen RM, Beuling EA,Spaargaren M, Pals ST.
    J Exp Med. 2000 Oct 16;192(8):1115-24.

    Contact

    Email: marcel.spaargaren@amsterdamumc.nl

    Keywords

    Lymphoma | multiple myeloma | kinase | microenvironment | cell adhesion | target discovery