Lymphoma and Myeloma Center Amsterdam

Amsterdam, Netherlands

Lymphoma and Myeloma Center Amsterdam

Amsterdam, Netherlands
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van Keimpema M.,Lymphoma and Myeloma Center Amsterdam | Gruneberg L.J.,Lymphoma and Myeloma Center Amsterdam | Schilder-Tol E.J.M.,Lymphoma and Myeloma Center Amsterdam | Oud M.E.C.M.,Lymphoma and Myeloma Center Amsterdam | And 5 more authors.
Haematologica | Year: 2017

The forkhead transcription factor FOXP1 is generally regarded as an oncogene in activated B cell-like diffuse large B-cell lymphoma. Previous studies have suggested that a small isoform of FOXP1 rather than full-length FOXP1, may possess this oncogenic activity. Corroborating those studies, we herein show that activated B cell-like diffuse large B-cell lymphoma cell lines and primary activated B cell-like diffuse large B-cell lymphoma cells predominantly express a small FOXP1 isoform, and that the 5’-end of the Foxp1 gene is a common insertion site in murine lymphomas in leukemia virus- and transposon- mediated insertional mutagenesis screens. By combined mass spectrometry, (quantative) reverse transcription polymerase chain reaction/ sequencing, and small interfering ribonucleic acid-mediated gene silencing, we determined that the small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma lacks the N-terminal 100 amino acids of full-length FOXP 1. Aberrant overexpression of this FOXP1 isoform (ΔN100) in primary human B cells revealed its oncogenic capacity; it repressed apoptosis and plasma cell differentiation. However, no difference in potency was found between this small FOXP1 isoform and full-length FOXP 1. Furthermore, overexpression of full-length FOXP1 or this small FOXP1 isoform in primary B cells and diffuse large B-cell lymphoma cell lines resulted in similar gene regulation. Taken together, our data indicate that this small FOXP1 isoform and full-length FOXP1 have comparable oncogenic and transcriptional activity in human B cells, suggesting that aberrant expression or overexpression of FOXP1, irrespective of the specific isoform, contributes to lymphomagenesis. These novel insights further enhance the value of FOXP1 for the diagnostics, prognostics, and treatment of diffuse large B-cell lymphoma patients. © 2017 Ferrata Storti Foundation.


Te Raa G.D.,University of Amsterdam | Derks I.A.M.,University of Amsterdam | Navrkalova V.,Masaryk University | Skowronska A.,University of Birmingham | And 17 more authors.
Leukemia | Year: 2015

Mutations or deletions in TP53 or ATM are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with ATM aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (n=110) containing ATM, SF3B1 and TP53 gene defects. Next, we applied a newly developed multiplex assay for p53ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly, SF3B1 mutated samples without concurrent ATM and TP53 aberrations (sole SF3B1) displayed partially defective ATMp53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast, NOTCH1 or KN-RAS mutated CLL displayed normal responses in p53ATM target gene induction and apoptosis. In sole SF3B1 mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage andor an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with SF3B1 mutations. © 2015 Macmillan Publishers Limited.


Te Raa G.D.,University of Amsterdam | Pascutti M.F.,University of Amsterdam | Garcia-Vallejo J.J.,VU University Amsterdam | Reinen E.,University of Amsterdam | And 10 more authors.
Blood | Year: 2014

In chronic lymphocytic leukemia (CLL), CD8+ T cells exhibit features of exhaustion and impaired functionality. Yet, reactivations of latent viruses such as cytomegalovirus (CMV) areuncommon in untreatedCLL, suggesting that antiviral responses areuncompromised. We analyzed phenotypical and functional characteristics of CMV-specific CD8+ T cells in CLL patients in comparison with age-matched healthy controls (HCs). Despite increased expression of the inhibitory receptors PD1, CD160, and CD244 on total CD8+ T cells in CLL, expression levels of these markers were decreased on CMV-tetramer+ CD8+ T cells. Second, cytokine production upon stimulation with both phorbol 12-myristate 13-acetate/ ionomycin and CMV-peptide-loaded antigen-presenting cells was intact in CMV-tetramer + CD8+ T cells. Third, CMV-tetramer+ CD8 + T cells of CLL patients and HCs were equally effective in killing CMV-peptide-loaded target cells. Finally, quantitative imaging flow cytometry revealed that the proportion of CD8+ T cells forming immunologic synapses with CMV-peptide-loaded B cells was intact. In conclusion, despite evidence for global T-cell dysfunction in CLL, we show here that CLL-derived CMV-specific CD8+ T cells display lower expression of exhaustion markers and are functionally intact. These data indicate that the changes in the T-cell compartment in CLL may be more heterogeneous than presently assumed. © 2014 by The American Society of Hematology.


Eldering E.,Lymphoma and Myeloma Center Amsterdam | van Oers M.H.,Lymphoma and Myeloma Center Amsterdam | Kater A.P.,Lymphoma and Myeloma Center Amsterdam
Leukemia Research | Year: 2013

Chronic lymphocytic leukemia (CLL) is still incurable, with considerable resistance to the standard therapy. CLL cells receive anti-apoptotic and pro-proliferation stimuli in lymph nodes and bone marrow, mainly through B cell receptor activation and TNF-receptor family ligation. In recent years, the focus for finding new drugs has shifted to blocking signals from the microenvironment. Novel therapeutical agents interfere with these microenvironmental interactions, and include inhibitors of kinases Syk, Btk and PI3Kδ. In this review we will focus on the microenvironmental interactions of CLL and the role of tyrosine kinases. Furthermore, early results from clinical trials with kinase inhibitors are discussed. © 2013 Elsevier Ltd.


Kater A.P.,Lymphoma and Myeloma Center Amsterdam | Tonino S.H.,Lymphoma and Myeloma Center Amsterdam | Egle A.,Paracelsus Medical University | Ramsay A.G.,King's College London
Blood | Year: 2014

Immunotherapy has emerged as a viable clinical strategy to harness endogenous antitumor T-cell immunity. Lenalidomide is anoralimmunomodulatorydrugthat repairs antitumor T-cell function and is showing efficacy in ongoing chronic lymphocytic leukemia (CLL) and lymphoma clinical trials. This article focuses on advances in our understanding of its mechanism of action in the tumor microenvironment and provides a clinical update in CLL. Challenges associated with this drug and its potential use in the targeted drug treatment era are discussed. (Blood. 2014; 124(14):2184-2189). © 2014 by The American Society of Hematology.


Kater A.P.,Lymphoma and Myeloma Center Amsterdam | Tonino S.H.,Lymphoma and Myeloma Center Amsterdam | Beckers M.M.,University of Groningen | Daenen S.,University of Groningen | And 4 more authors.
Leukemia Research | Year: 2014

Resistance to chemotherapy-induced apoptosis in CLL is associated with overexpression of antiapoptotic proteins induced by signals from the microenvironment. In vitro, dasatinib effectively inhibits expression of anti-apoptotic regulators and restores fludarabine sensitivity in activated CLL. The aim of this study was to evaluate efficacy of one cycle of dasatinib monotherapy (100mg/day, days 1-28) followed by combination of dasatinib with fludarabine (40mg/m2/day, days 1-3 every 28 day) for a total of 6 cycles in fludarabine-refractory CLL. The primary endpoint was overall response rate according to the IWCLL'08 criteria.20 patients were enrolled: 18 completed at least one cycle of treatment of which 67% finished at least 2 cycles of combination treatment. 3 of these 18 patients reached a formal PR (16.7%). Majority of patients obtained some reduction in lymph node (LN) size. Most frequent toxicity was related to myelosuppression. NF-κB RNA expression levels of circulating CLL cells decreased whereas the levels of pro-apoptotic NOXA increased during treatment. In conclusion, dasatinib/fludarabine combination has modest clinical efficacy in fludarabine-refractory patients. © 2013 Elsevier Ltd.


PubMed | University of Amsterdam, Sanquin Research and Landsteiner Laboratory, Lymphoma and Myeloma Center Amsterdam, Netherlands Cancer Institute and Sanofi S.A.
Type: Journal Article | Journal: Leukemia | Year: 2016

The phosphoinositide 3-kinases (PI3Ks) are critical components of the B-cell receptor (BCR) pathway and have an important role in the pathobiology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3K block BCR-mediated cross-talk between CLL cells and the lymph node microenvironment and provide significant clinical benefit to CLL patients. However, the PI3K inhibitors applied thus far have limited direct impact on leukemia cell survival and thus are unlikely to eradicate the disease. The use of inhibitors of multiple isoforms of PI3K might lead to deeper remissions. Here we demonstrate that the pan-PI3K/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) was more pro-apoptotic to CLL cells--irrespective of their ATM/p53 status--than PI3K or PI3K isoform selective inhibitors. Furthermore, SAR245409 blocked CLL survival, adhesion and proliferation. Moreover, SAR245409 was a more potent inhibitor of T-cell-mediated production of cytokines, which support CLL survival. Taken together, our in vitro data provide a rationale for the evaluation of a pan-PI3K inhibitor in CLL patients.


PubMed | Lymphoma and Myeloma Center Amsterdam, University Utrecht, Erasmus Medical Center and Hubrecht Institute for Developmental Biology and Stem Cell Research
Type: Journal Article | Journal: Blood | Year: 2015

Expression of the forkhead transcription factor FOXP1 is essential for early B-cell development, whereas downregulation of FOXP1 at the germinal center (GC) stage is required for GC B-cell function. Aberrantly high FOXP1 expression is frequently observed in diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma, being associated with poor prognosis. Here, by gene expression analysis upon ectopic overexpression of FOXP1 in primary human memory B cells (MBCs) and B-cell lines, combined with chromatin immunoprecipitation and sequencing, we established that FOXP1 directly represses expression of PRDM1, IRF4, and XBP1, transcriptional master regulators of plasma cell (PC) differentiation. In accordance, FOXP1 is prominently expressed in primary human naive and MBCs, but expression strongly decreases during PC differentiation. Moreover, as compared with immunoglobulin (Ig) M(+) MBCs, IgG(+) MBCs combine lower expression of FOXP1 with an enhanced intrinsic PC differentiation propensity, and constitutive (over)expression of FOXP1 in B-cell lines and primary human MBCs represses their ability to differentiate into PCs. Taken together, our data indicate that proper control of FOXP1 expression plays a critical role in PC differentiation, whereas aberrant expression of FOXP1 might contribute to lymphomagenesis by blocking this terminal B-cell differentiation.


PubMed | University of Amsterdam, Lymphoma and Myeloma Center Amsterdam and Hubrecht Institute
Type: Journal Article | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2016

The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto- and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.


Spaargaren M.,University of Amsterdam | Spaargaren M.,Lymphoma and Myeloma Center Amsterdam | De Rooij M.F.M.,University of Amsterdam | Kater A.P.,Lymphoma and Myeloma Center Amsterdam | And 3 more authors.
Oncogene | Year: 2015

The treatment of chronic lymphocytic leukemia (CLL) with inhibitors targeting B cell receptor signaling and other survival mechanisms holds great promise. Especially the early clinical success of Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), has received widespread attention. In this review we will focus on the fundamental and clinical aspects of BTK inhibitors in CLL, with emphasis on Ibrutinib as the best studied of this class of drugs. Furthermore, we summarize recent laboratory as well as clinical findings relating to the first cases of Ibrutinib resistance. Finally, we address combination strategies with Ibrutinib, and attempt to extrapolate its current status to the near future in the clinic. © 2015 Macmillan Publishers Limited All rights reserved.

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