Publications
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Våtsveen, Thea Kristin; Giliberto, Mariaserena; Björnsdottir, Valgerdur; Centonze, Federica Grazia; Besse, Andrej & Frey, Yannick
[Show all 19 contributors for this article]
(2025).
Targeting proteostasis in multiple myeloma through inhibition of LTK.
Leukemia.
ISSN 0887-6924.
39(9),
p. 2237–2245.
doi:
10.1038/s41375-025-02682-8.
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Multiple myeloma (MM) cells secrete high levels of immunoglobulin and are therefore addicted to mechanisms that maintain proteome homeostasis (proteostasis). While proteasome inhibitors that target the degradative aspect of proteostasis have proven effective, only limited attempts have been made to target protein secretion. Here we show that the receptor tyrosine kinase LTK is a regulatory node in the proteostasis network that responds to secretory load and helps cells maintain a high secretory output. LTK is a highly similar paralog to ALK and by repurposing existing ALK inhibitors, we demonstrate that targeting LTK causes immunoglobulin retention, ER stress and subsequent apoptosis of primary MM cells, even in patients refractory to proteasome inhibitors. Thus, LTK is a novel therapeutic target in the biosynthetic pathway of proteostasis, with significant potential for MM treatment.
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Behsen, Alenka Djarmila; Holien, Toril; Micci, Francesca; Rye, Morten Beck; Rasmussen, Jenny Malm & Andersen, Kristin
[Show all 11 contributors for this article]
(2024).
Cell surface marker heterogeneity in human myeloma cell lines for modeling of disease and therapy.
Scientific Reports.
14:28805(1),
p. 1–8.
doi:
10.1038/s41598-024-80263-y.
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Multiple myeloma (MM) is a hematological malignancy originating from plasma cells. Genetically, MM is categorized into two subtypes: hyperdiploid and non-hyperdiploid tumors, with distinct chromosomal characteristics. Human myeloma cell lines (HMCLs) are instrumental in understanding MM and identifying therapeutic targets. However, their utility depends on their resemblance to patient-derived cells. We analyzed protein expression of cell surface markers, including myeloma drug targets and immunotherapy-relevant markers, in nine HMCLs using flow cytometry. RNAseq analysis was performed to correlate protein expression with transcriptomic data. While five cell surface markers (CD47, CD49d, CD138, CD269 (BCMA), and GPRC5D) were highly expressed and three (CD19, CD20, and CD117) were low or negative across cell lines, heterogenous expression was observed for the 16 remaining markers. A comparative study with patient-derived transcriptomic data indicated that four of our six in-house HMCLs closely resembled patient disease. Furthermore, our hyperdiploid HMCLs correlated better with hyperdiploid than non-hyperdiploid patient samples. Here, we also describe three previously uncharacterized HMCLs; IH-1, URVIN and FOLE. Our findings underscore the importance of evaluating surface protein expression in HMCLs when modeling MM. The observed variations in expression levels emphasize the need for a strategic selection of cell lines based on the study’s objectives.
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Huse, Kanutte; Bai, Baoyan; Hilden, Vera Irene; Bollum, Lise Kristin; Våtsveen, Thea Kristin & Munthe, Ludvig Andre
[Show all 10 contributors for this article]
(2022).
Mechanism of CD79A and CD79B support for IgM+ B cell fitness through B cell receptor surface expression.
Journal of Immunology.
ISSN 0022-1767.
209(10),
p. 2042–2053.
doi:
10.4049/jimmunol.2200144.
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he BCR consists of surface-bound Ig and a heterodimeric signaling unit comprised of CD79A and CD79B. Upon cognate Ag recognition, the receptor initiates important signals for B cell development and function. The receptor also conveys Ag-independent survival signals termed tonic signaling. Although the requirement of a CD79A/CD79B heterodimer for BCR complex assembly and surface expression is well established based on mice models, few studies have investigated this in human mature B cells. In this study, we found that human tonsillar B cells with high surface expression of IgM or IgG had potentiated BCR signaling compared with BCRlow cells, and high IgM expression in germinal center B cells was associated with reduced apoptosis. We explored the mechanism for IgM surface expression by CRISPR/Cas9-induced deletion of CD79A or CD79B in four B lymphoma cell lines. Deletion of either CD79 protein caused loss of surface IgM in all cell lines and reduced fitness in three. From two cell lines, we generated stable CD79A or CD79B knockout clones and demonstrated that loss of CD79A or CD79B caused a block in N-glycan maturation and accumulation of immature proteins, compatible with retention of BCR components in the endoplasmic reticulum. Rescue experiments with CD79B wild-type restored surface expression of CD79A and IgM with mature glycosylation, whereas a naturally occurring CD79B G137S mutant disrupting CD79A/CD79B heterodimerization did not. Our study highlights that CD79A and CD79B are required for surface IgM expression in human B cells and illuminates the importance of the IgM expression level for signaling and fitness.
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Sanjiv, Kumar; Calderón-Montaño, José Manuel; Pham, Therese M.; Erkers, Tom; Tsuber, Viktoriia & Almlöf, Ingrid
[Show all 32 contributors for this article]
(2021).
MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia.
Cancer Research.
ISSN 0008-5472.
81(22),
p. 5733–5744.
doi:
10.1158/0008-5472.CAN-21-0061.
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Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, exhibiting high levels of reactive oxygen species (ROS). ROS levels have been suggested to drive leukemogenesis and is thus a potential novel target for treating AML. MTH1 prevents incorporation of oxidized nucleotides into the DNA to maintain genome integrity and is upregulated in many cancers. Here we demonstrate that hematologic cancers are highly sensitive to MTH1 inhibitor TH1579 (karonudib). A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubicin. Furthermore, TH1579 killed primary human AML blast cells (CD45+) as well as chemotherapy resistance leukemic stem cells (CD45+Lin−CD34+CD38−), which are often responsible for AML progression. TH1579 killed AML cells by causing mitotic arrest, elevating intracellular ROS levels, and enhancing oxidative DNA damage. TH1579 showed a significant therapeutic window, was well tolerated in animals, and could be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the preclinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rationale to investigate the clinical usefulness of TH1579 in AML in an ongoing clinical phase I trial.
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Oksvold, Morten Pedersen; Berglund, Ulrika Warpman; Gad, Helge; Bai, Baoyan; Stokke, Trond & Rein, Idun Dale
[Show all 14 contributors for this article]
(2021).
Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma.
Scientific Reports.
11(1).
doi:
10.1038/s41598-021-85613-8.
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Abstract Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma.
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Våtsveen, Thea Kristin; Myhre, Marit Renee; Steen, Chloe Beate; Wälchli, Sébastien; Lingjærde, Ole Christian & Bai, Baoyan
[Show all 14 contributors for this article]
(2018).
Artesunate shows potent anti-tumor activity in B-cell lymphoma.
Journal of Hematology & Oncology.
11:23,
p. 1–12.
doi:
10.1186/s13045-018-0561-0.
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Background Although chemo-immunotherapy has led to an improved overall survival for most B-cell lymphoma types, relapsed and refractory disease remains a challenge. The malaria drug artesunate has previously been identified as a growth suppressor in some cancer types and was tested as a new treatment option in B-cell lymphoma. Methods We included artesunate in a cancer sensitivity drug screen in B lymphoma cell lines. The preclinical properties of artesunate was tested as single agent in vitro in 18 B-cell lymphoma cell lines representing different histologies and in vivo in an aggressive B-cell lymphoma xenograft model, using NSG mice. Artesunate-treated B lymphoma cell lines were analyzed by functional assays, gene expression profiling, and protein expression to identify the mechanism of action. Results Drug screening identified artesunate as a highly potent anti-lymphoma drug.Artesunate induced potent growth suppression in most B lymphoma cells with an IC50 comparable to concentrations measured in serum from artesunate-treated malaria patients, while leaving normal B-cells unaffected. Artesunate markedly inhibited highly aggressive tumor growth in a xenograft model. Gene expression analysis identified endoplasmic reticulum (ER) stress and the unfolded protein response as the most affected pathways and artesunate-induced expression of the ER stress markers ATF-4 and DDIT3 was specifically upregulated in malignant B-cells, but not in normal B-cells. In addition, artesunate significantly suppressed the overall cell metabolism, affecting both respiration and glycolysis. Conclusions Artesunate demonstrated potent apoptosis-inducing effects across a broad range of B-cell lymphoma cell lines in vitro, and a prominent anti-lymphoma activity in vivo, suggesting it to be a relevant drug for treatment of B-cell lymphoma.
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Vandsemb, Esten Nymoen; Bertilsson, Helena; Abdollahi, Pegah; Størkersen, Øystein; Våtsveen, Thea Kristin & Rye, Morten Beck
[Show all 9 contributors for this article]
(2016).
Phosphatase of regenerating liver 3 (PRL-3) is overexpressed in human prostate cancer tissue and promotes growth and migration.
Journal of Translational Medicine.
14(71).
doi:
10.1186/s12967-016-0830-z.
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Background: PRL-3 is a phosphatase implicated in oncogenesis in multiple cancers. In some cancers, notably carcinomas, PRL-3 is also associated with inferior prognosis and increased metastatic potential. In this study we investigated the expression of PRL-3mRNA in fresh-frozen samples from patients undergoing radical prostatectomy because of prostate cancer (PC) and the biological function of PRL-3 in prostate cancer cells. Methods: Samples from 41 radical prostatectomy specimens (168 samples in total) divided into low (Gleason score ≤ 6), intermediate (Gleason score = 7) and high (Gleason score ≥ 8) risk were analyzed with gene expression profiling and compared to normal prostate tissue. PRL-3was identified as a gene with differential expression between healthy and cancerous tissue in these analyses. We used the prostate cancer cell lines PC3 and DU145 and a small molecular inhibitor of PRL-3 to investigate whether PRL-3 had a functional role in cancer. Relative ATP-measurement and thymidine incorporation were used to assess the effect of PRL-3 on growth of the cancer cells. We performed an in vitro scratch assay to investigate the involvement of PRL-3 in migration. Immunohistochemistry was used to identify PRL-3 protein in prostate cancer primary tumor and corresponding lymph node metastases. Results: Compared to normal prostate tissue, the prostate cancer tissue expressed a significantly higher level of PRL-3. We found PRL-3 to be present in both PC3 and DU145, and that inhibition of PRL-3 led to growth arrest and apoptosis in these two cell lines. Inhibition of PRL-3 led to reduced migration of the PC3 cells. Immunohistochemistry showed PRL-3 expression in both primary tumor and corresponding lymph node metastases. Conclusions: PRL-3 mRNA was expressed to a greater extent in prostate cancer tissue compared to normal prostate tissue. PRL-3 protein was expressed in both prostate cancer primary tumor and corresponding lymph node metastases. The results from our in vitro assays suggest that PRL-3 promotes growth and migration in prostate cancer. In conclusion, these results imply that PRL-3 has a role in the pathogenesis of prostate cancer.
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Våtsveen, Thea Kristin; Sponaas, Anne Marit; Tian, Erming; Zhang, Qing; Misund, Kristine & Sundan, Anders
[Show all 9 contributors for this article]
(2016).
Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro.
Journal of Hematology & Oncology.
9(75).
doi:
10.1186/s13045-016-0306-x.
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Background: Multiple myeloma is an incurable complex disease characterized by clonal proliferation of malignant plasma cells in a hypoxic bone marrow environment. Hypoxia-dependent erythropoietin (EPO)-receptor (EPOR) signaling is central in various cancers, but the relevance of EPOR signaling in multiple myeloma cells has not yet been thoroughly investigated. Methods: Myeloma cell lines and malignant plasma cells isolated from bone marrow of myeloma patients were used in this study. Transcript levels were analysed by quantitative PCR and cell surface levels of EPOR in primary cells by flow cytometry. Knockdown of EPOR by short interfering RNA was used to show specific EPOR signaling in the myeloma cell line INA-6. Flow cytometry was used to assess viability in primary cells treated with EPO in the presence and absence of neutralizing anti-EPOR antibodies. Gene expression data for total therapy 2 (TT2), total therapy 3A (TT3A) trials and APEX 039 and 040 were retrieved from NIH GEO omnibus and EBI ArrayExpress. Results: We show that the EPOR is expressed in myeloma cell lines and in primary myeloma cells both at the mRNA and protein level. Exposure to recombinant human EPO (rhEPO) reduced viability of INA-6 myeloma cell line and of primary myeloma cells. This effect could be partially reversed by neutralizing antibodies against EPOR. In INA-6 cells and primary myeloma cells, janus kinase 2 (JAK-2) and extracellular signal regulated kinase 1 and 2 (ERK-1/2) were phosphorylated by rhEPO treatment. Knockdown of EPOR expression in INA-6 cells reduced rhEPO-induced phospo-JAK-2 and phospho-ERK-1/2. Co-cultures of primary myeloma cells with bone marrow-derived stroma cells did not protect the myeloma cells from rhEPO-induced cell death. In four different clinical trials, survival data linked to gene expression analysis indicated that high levels of EPOR mRNA were associated with better survival. Conclusions: Our results demonstrate for the first time active EPOR signaling in malignant plasma cells. EPO-mediated EPOR signaling reduced the viability of myeloma cell lines and of malignant primary plasma cells in vitro. Our results encourage further studies to investigate the importance of EPO/EPOR in multiple myeloma progression and treatment. Trial registration: [Trial registration number for Total Therapy (TT) 2: NCT00083551 and TT3: NCT00081939].
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Olsen, Oddrun Elise; Wader, Karin Fahl; Misund, Kristine; Våtsveen, Thea Kristin; Rø, Torstein Baade & Mylin, Anne K.
[Show all 13 contributors for this article]
(2014).
Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin.
Blood Cancer Journal.
4.
doi:
10.1038/bcj.2014.16.
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Multiple myeloma is a malignancy of plasma cells predominantly located in the bone marrow. A number of bone morphogenetic proteins (BMPs) induce apoptosis in myeloma cells in vitro, and with this study we add BMP-9 to the list. BMP-9 has been found in human serum at concentrations that inhibit cancer cell growth in vitro. We here show that the level of BMP-9 in serum was elevated in myeloma patients (median 176 pg/ml, range 8–809) compared with healthy controls (median 110 pg/ml, range 8–359). BMP-9 was also present in the bone marrow and was able to induce apoptosis in 4 out of 11 primary myeloma cell samples by signaling through ALK2. BMP-9-induced apoptosis in myeloma cells was associated with c-MYC downregulation. The effects of BMP-9 were counteracted by membrane-bound (CD105) or soluble endoglin present in the bone marrow microenvironment, suggesting a mechanism for how myeloma cells can evade the tumor suppressing activity of BMP-9 in multiple myeloma.
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Rampa, Christoph Samuel; Tian, Erming; Våtsveen, Thea Kristin; Buene, Glenn; Slørdahl, Tobias Schmidt & Børset, Magne
[Show all 8 contributors for this article]
(2014).
Identification of the source of elevated hepatocyte growth factor levels in multiple myeloma patients.
Biomarker Research.
2(1).
doi:
10.1186/2050-7771-2-8.
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Background
Hepatocyte growth factor (HGF) is a pleiotropic cytokine which can lead to cancer cell proliferation, migration and metastasis. In multiple myeloma (MM) patients it is an abundant component of the bone marrow. HGF levels are elevated in 50% of patients and associated with poor prognosis. Here we aim to investigate its source in myeloma.
Methods
HGF mRNA levels in bone marrow core biopsies from healthy individuals and myeloma patients were quantified by real-time PCR. HGF gene expression profiling in CD138+ cells isolated from bone marrow aspirates of healthy individuals and MM patients was performed by microarray analysis. HGF protein concentrations present in peripheral blood of MM patients were measured by enzyme-linked immunosorbent assay (ELISA). Cytogenetic status of CD138+ cells was determined by fluorescence in situ hybridization (FISH) and DNA sequencing of the HGF gene promoter. HGF secretion in co-cultures of human myeloma cell lines and bone marrow stromal cells was measured by ELISA.
Results
HGF gene expression profiling in both bone marrow core biopsies and CD138+ cells showed elevated HGF mRNA levels in myeloma patients. HGF mRNA levels in biopsies and in myeloma cells correlated. Quantification of HGF protein levels in serum also correlated with HGF mRNA levels in CD138+ cells from corresponding patients. Cytogenetic analysis showed myeloma cell clones with HGF copy numbers between 1 and 3 copies. There was no correlation between HGF copy number and HGF mRNA levels. Co-cultivation of the human myeloma cell lines ANBL-6 and JJN3 with bone marrow stromal cells or the HS-5 cell line resulted in a significant increase in secreted HGF.
Conclusions
We here show that in myeloma patients HGF is primarily produced by malignant plasma cells, and that HGF production by these cells might be supported by the bone marrow microenvironment. Considering the fact that elevated HGF serum and plasma levels predict poor prognosis, these findings are of particular importance for patients harbouring a myeloma clone which produces large amounts of HGF.
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Müller, Rebekka; Misund, Kristine; Holien, Toril; Bachke, Siri; Gilljam, Karin Margaretha & Våtsveen, Thea Kristin
[Show all 10 contributors for this article]
(2013).
Targeting Proliferating Cell Nuclear Antigen and Its Protein Interactions Induces Apoptosis in Multiple Myeloma Cells.
PLOS ONE.
8(7).
doi:
10.1371/journal.pone.0070430.
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Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA) is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM). Thus inhibiting PCNA’s protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell-penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells’ sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX-101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment.
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Vatsveen, TK; Våtsveen, Thea Kristin; Tian, Erming; Kresse, Stine H; Meza-Zepada, Leonardo & Meza, Leonardo Zepeda
[Show all 14 contributors for this article]
(2009).
OH-2, a hyperdiploid myeloma cell line without an IGH translocation, has a complex translocation juxtaposing MYC near MAFB and the IGK locus.
Leukemia Research.
ISSN 0145-2126.
33(12),
p. 1670–1677.
doi:
10.1016/j.leukres.2009.03.001.
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Multiple myeloma can be classified into hyperdiploid (HRD) (with 48–74 chromosomes) and non-hyperdiploid tumors (usually with immunoglobulin heavy chain translocations). The OH-2 human myeloma cell line (HMCL) retains the same HRD genotype as the primary tumor, with extra copies of chromosomes 3, 7, 15, 19, and 21. Both OH-2 and primary cells have a complex secondary translocation in which the IGK 3′ enhancer is inserted between MYC and MAFB, resulting in dysregulation of both oncogenes. OH-2 provides a unique example of an HMCL and the corresponding primary tumor that are shown to share the same HRD genotype
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Våtsveen, Thea Kristin; Brenne, Anne-Tove; Dai, HY; Waage, Anders; Sundan, Anders & Børset, Magne
(2009).
FGFR3 is expressed and is important for survival in INA-6, a human myeloma cell line without a t(4;14).
European Journal of Haematology.
ISSN 0902-4441.
83(5),
p. 471–476.
doi:
10.1111/j.1600-0609.2009.01312.x.
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Kongsrud, Karoline; Tvedt, Charlotte Hop; Christensen, Thea Josefine; Caulier, Benjamin William; Spasevska, Ivana & Hilden, Vera Irene
[Show all 14 contributors for this article]
(2025).
B-cell Lymphoma Patient-Derived Xenograft Models for improved preclinical in vivo testing.
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The treatment landscape for B-cell non-Hodgkin lymphoma (B-NHL) has expanded dramatically in recent years, including advanced immunotherapies and targeted drugs. Yet, early relapse is still associated with an adverse prognosis, highlighting the need for new treatment options. For identification of potent new treatment strategies and combinatorial approaches, better preclinical models are needed that can facilitate testing at larger scale. Patient-derived xenograft (PDX) models are in vivo models established by engrafting tumor fragments from cancer patients into immunodeficient mice. The PDX tumors can retain the molecular features including clonal heterogeneity of the original tumor. Our aim is to establish relevant PDX models from B-cell lymphoma tumors for in vivo and ex vivo testing of drugs and immunotherapy.
We have successfully established PDX models from diffuse large B-cell lymphoma (DLBCL, n= 3) and mantle cell lymphoma (MCL, n= 2). For phenotypical characterization, we have developed a 32-marker spectral flow cytometry panel to identify key B cell features (CD10, CD19, CD20, CD22, CD37, CD79B, and Ig heavy and Ig light chains) and other immune cells including T cell subsets and myeloid cells. In addition, targeted sequencing will be used to determine if the mutational composition is stable over time, across different PDX generations. These results will facilitate selection of the best models for future studies. As proof-of -concept, we have used one of the MCL PDX models to test the efficacy of kinase inhibitors and the efficacy of CD19 CAR T cells. These models might support the development of personalized treatment strategies.
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Våtsveen, Thea Kristin & Munthe, Ludvig Andre
(2025).
Targeting Proteostasis in Multiple Myeloma through Inhibition of Leukocyte Tyrosine Kinase (LTK).
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Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Waage, Anders & Sundan, Anders
(2013).
Dependency on c-MYC in multiple myeloma.
Cancer Research.
ISSN 0008-5472.
73(8).
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Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Waage, Anders & Sundan, Anders
(2013).
Dependency on c-MYC in multiple myeloma.
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Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Waage, Anders & Sundan, Anders
(2012).
Dependency on c-MYC in multiple myeloma.
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Våtsveen, Thea Kristin; Brenne, Anne-Tove; Dai, Hong Yan; Waage, Anders; Sundan, Anders & Børset, Magne
(2009).
FGFR3 Expression Is Important In The t(4;14)NEG INA-6 HMCL.
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Våtsveen, Thea Kristin; Brenne, Anne-Tove; Dai, Hong Yan; Waage, Anders; Sundan, Anders & Børset, Magne
(2009).
FGFR3 is expressed and important for survival in INA-6, a human myeloma cell line without a t(4;14).
Full text in Research Archive
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Holien, Toril; Brede, Gaute; Våtsveen, Thea Kristin; Børset, Magne; Waage, Anders & Sundan, Anders
(2009).
Bone morphogenetic proteins induce downregulation of c-Myc and c-Myc target genes in multiple myeloma.
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Våtsveen, Thea Kristin; Brenne, Anne-Tove; Dai, Hong Yan; Waage, Anders; Sundan, Anders & Børset, Magne
(2009).
FGFR3 Expression Is Important In The t(4;14)NEG INA-6 HMCL.
Clinical Lymphoma & Myeloma.
ISSN 1557-9190.
9,
p. S103–S103.
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1. Background: Fibroblast growth factor receptor 3 (FGFR3) might play a role in the survival and proliferation of myeloma (MM) cells. Primary MM cells and MM cell lines (HMCL) with t(4;14)POS express FGFR3 in 75% of the cases.
2. Aim: If FGFR3 plays an important carcinogenic role, one might expect other genetic aberrations than t(4;14) POS to lead to expression of the gene. We show data suggesting that gene amplification is another mechanism leading to expression of FGFR3.
3. Methods: Fluorescence in situ hybridization with locus-specific probes for FGFR3 and MMSET was used on metaphase spreads of the t(11;14)POS INA-6, and array-CGH was used to look at the genomic alterations. Western Blot and qRT-PCR detected the FGFR3 expression. To determine the functional role of the receptor, small-molecule FGFR3-inhibitors SU-5402 and PD-173074 were used in proliferation studies and viability studies. The t(4;14) POS HMCLs IH-1 was used as a positive control and OH-2 without FGFR3 expression was used as a negative control. All three HMCLs are IL-6 dependant. FGFR3 was sequenced in INA-6 and IH-1 to look for activating mutations. MMSET expression was also determined by qRT-PCR.
4. Results: The FGFR3 was present in INA-6 cells although the cell line is t(4;14)NEG. In INA-6 the expression of FGFR3 is dependant on IL-6, and the expression of FGFR3 is decreased when cells are starved for IL-6 over night. The same level of decreased FGFR3 was not seen in IL-6 deprived IH-1 cells. INA-6 has a trisomy of chromosome 4 and there was a duplication of the 4p16.3 locus on one 4p on chromosome 4. The FGFR3 inhibitors, SU-5402 and PD-173074, each reduced proliferation of INA-6 cells, both in the presence and in the absence of aFGF. Similar inhibition was seen in IH-1 cells, a t(4;14)POS HMCL, whereas OH-2 cells, HMCL without FGFR3 expression, were insensitive to the drugs. The same was also seen when looking at cell viability with flow cytometry. The FGFR3 was not mutated in IH-1 or INA-6 determined by sequencing. MMSET in INA-6 was close to the expression in OH-2 and significantly lower than in IH-1.
5. Summary/Conclusion: INA-6 expresses wild type FGFR3 without having a t(4;14)POS. Amplification of the FGFR3 might cause the expression. The FGFR3 level decreases when the cells are deprived of IL-6. The alternative mode of aberrant FGFR3 expression shown in INA-6 cells is supportive of an oncogenic role for this receptor in MM. Since INA-6 it does not express MMSET at a high level, contrary to all the t(4;14)POS cell lines and, hence, lacks the IGH/MMSET fusion transcript, it might be useful as a model system for investigating FGFR3’s role in MM cells independently of the interaction of high levels of MMSET.
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Våtsveen, Thea Kristin; Dai, Hong Yan; Kresse, SH; Sundan, Anders & Børset, Magne
(2007).
OH-2; a human multiple myeloma cell line without IgH translocation.
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Våtsveen, Thea Kristin; Engesvold, Ingeborg & Furre, Tone
(2007).
cIg-FISH ved cytogenetiske avvik hos myelomatosepasienter.
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Våtsveen, Thea Kristin & Børset, Magne
(2007).
MiR-21 is over-expressed in cytokine stimulated multiple myeloma cell lines.
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Våtsveen, Thea Kristin; Dai, Hong Yan; Kresse, SH; Sundan, Anders & Børset, Magne
(2007).
OH-2; a human multiple myeloma cell line without IgH translocation.
Haematologica.
ISSN 0390-6078.
92(6),
p. 1–246.
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Hov, Håkon; Våtsveen, Thea Kristin; Waage, Anders; Sundan, Anders & Børset, Magne
(2006).
Induction of Cyclin D1 by HGF, IGF-1 and IL-6 in a Human Myeloma Cell Line with a t(11:14) Translocation.
Blood.
ISSN 0006-4971.
108,
p. 5055–5055.
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Våtsveen, Thea Kristin; Børset, Magne; Sundan, Anders & Waage, Anders
(2009).
Genetic Aberrationsin Myeloma Cells.
Norges teknisk-naturvitenskapelige universitet.
ISSN 9788247115442.
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Genetiske avvik i myelomceller Myelomatose (beinmargskreft) er kreft i plasmacellene i beinmargen. Det er den nest vanligste hematologiske kreftformen og rammer ca 300 personer i Norge hvert år. Kun 15% av pasientene er under 65 år. Det finnes ingen helbredende behandling for denne sykdommen, men i de siste årene har behandlingen blitt forbedret og i snitt lever pasientene nå i 5 år etter diagnosetidspunktet. Genetikken i myelomatosecellene er ikke godt kartlagt, men grovt kan sykdommen deles inn i to genetiske grupper basert på antall kromosom og tilstedeværelse av translokasjoner i genet for den tunge immunglobulingenet (IGH). Den ene typen, hyperdiploid myelomatose, har 48-74 kromosom og sjelden IGH-translokasjoner, mens den andre hovedtypen, ikke-hyperdiploide myelomatose, har under 48 eller over 74 kromosom og ofte IGHtranslokasjoner. Den hyperdiploide gruppen kjennetegnes ved at det ofte er tre kopier av minst fire av de åtte kromosomene 3, 5, 7, 9, 11, 15, 17, 19 og 21, men man vet enda ikke hva den grunnleggende genskaden som fører til kreftutviklingen er. Hos den ikke-hyperdiploide gruppen er det et fellestrekk at gen som er involvert i IGH-translokasjonen er den type gen som kan bidra i kreftutvikling. Når man studerer myelomatose i laboratoriet bruker man vanligvis cellelinjer som er udødeliggjorte celler fra myelomatosepasienter. Alle til nå publiserte cellelinjer er ikke-hyperdiploide, og derfor har mesteparten av laboratorieforskningen på myelomatose blitt gjort på celler som bare representerer halvparten av pasientene. I denne doktorgraden er det fokusert på genetikken til myelomatoseceller. Det er både lagt vekt på å beskrive cellelinjene i bruk på laboratoriet og å undersøke både generelle og spesifikke avvik i celler fra myelomatosepasienter. Første artikkel er en beskrivelse av cellelinjen OH-2 som ble etablert i Trondheim i 1992. Det viktigste funnet er at cellelinjen OH-2 er den første hyperdiploide cellelinjen som er beskrevet. Cellelinjen har tre kopier av kromosom 3, 7, 15 og 21 og den har ingen IGH-translokasjon. Den har derimot en del av IGK (Immunglobulin lettkjede kappa-genet) satt inn mellom genene MAFB og MYC i en kompleks translokasjon. Andre artikkel er en undersøkelse av Fibroblast vekstfaktor 3 (FGFR3). Cellelinjen INA-6 har ikke den vanlige translokasjonen mellom IGH og FGFR3, som er den eneste beskrevne årsaken til uttrykk av FGFR3 i myelomceller, men den uttrykker likevel FGFR3. INA-6 har i stedet en ekstra kopi av FGFR3, noe vi tror er skyld i uttrykket av FGFR3 i denne cellelinjen. Vi viser at uttrykket av FGFR3 er viktig i denne cellelinjen. Tredje artikkel beskriver fosfatase i regenerativ lever 3 (PRL3), som tidligere er vist å være overuttrykt i metastaser i andre kreftformer. Det er også vist at ekstra kopier av PRL3 genet er funnet i noen av disse metastasene. Vi undersøkte derfor om dette også var tilfellet i myelomatose. Det ser ikke ut til at ekstra kopier er utbredt i myelomatose, og det er mer sannsynlig at andre faktorer enn ekstra genkopier er årsaken til høyt nivå i myelomcellene undersøkt. Fjerde artikkel beskriver BCL3 som uttykkes i myelomceller som en respons på stimulering av forskjellige vekstfaktorer. BCL3 genet er involvert i translokasjoner i andre kreftformer og vi fant også en translokasjon i BCL3 locus i en pasient. Både PRL3 og BCL3 er høyt uttrykt i en undergruppe av pasienter med dårlig prognose, og begge genene/proteinene kan være viktige hos disse pasientene. Femte artikkel er en foreløpig analyse av genetisk avvik og kliniske parametre som blant annet Beta-2-mikroglobulin og beinlesjoner hos nydiagnostiserte myelomatosepasienter i Norge. Vi fant ingen spesielle korrelasjoner mellom de ulike parameterne ved diagnose. Arbeidet er utført i perioden 2006-2008 ved NTNU og St.Olavs hospital, med støtte fra Norges forskningsråd (NFR).
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Våtsveen, Thea Kristin & Johansen, Berit
(2005).
Analyser av genetiske avvik i myelomatose ved hjelp av fluorescens in situ hybridisering.
Institutt for biologi, NTNU.
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Sep. 28, 2018 12:19 PM
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