Thea Kristin Våtsveen

• 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. Show summary

  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.

• 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. ISSN 2045-2322. 11(1). doi: 10.1038/s41598-021-85613-8. Full text in Research Archive
• 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. Full text in Research Archive
• 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. ISSN 1756-8722. 11:23, p. 1–12. doi: 10.1186/s13045-018-0561-0. Full text in Research Archive
• Våtsveen, Thea Kristin; Børset, Magne; Dikic, Aida; Tian, Erming; Micci, Francesca & Lid, Ana Barragan [Show all 12 contributors for this article] (2016). VOLIN and KJON—Two novel hyperdiploid myeloma cell lines. Genes, Chromosomes and Cancer. ISSN 1045-2257. 55(11), p. 890–901. doi: 10.1002/gcc.22388.
• 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. ISSN 1756-8722. 9(75). doi: 10.1186/s13045-016-0306-x. Full text in Research Archive
• Nahi, Hareth; Våtsveen, Thea Kristin; Lund, Johan; Heeg, Bart M.S.; Preiss, Birgitte & Alici, Evren [Show all 16 contributors for this article] (2016). Proteasome inhibitors and IMiDs can overcome some high-risk cytogenetics in multiple myeloma but not gain 1q21. European Journal of Haematology. ISSN 0902-4441. 96(1), p. 46–54. doi: 10.1111/ejh.12546.
• 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. ISSN 1479-5876. 14(71). doi: 10.1186/s12967-016-0830-z. Full text in Research Archive
• Tian, Erming; Børset, Magne; Sawyer, Jeffrey R; Brede, Gaute; Våtsveen, Thea Kristin & Hov, Håkon [Show all 11 contributors for this article] (2015). Allelic mutations in noncoding genomic sequences construct novel transcription factor binding sites that promote gene overexpression. Genes, Chromosomes and Cancer. ISSN 1045-2257. 54(11), p. 692–701. doi: 10.1002/gcc.22280.
• 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. ISSN 2050-7771. 2(1). doi: 10.1186/2050-7771-2-8. Full text in Research Archive Show summary

  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.

• 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. ISSN 2044-5385. 4. doi: 10.1038/bcj.2014.16. Full text in Research Archive Show summary

  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.

• 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. ISSN 1932-6203. 8(7). doi: 10.1371/journal.pone.0070430. Full text in Research Archive
• Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Waage, Anders & Sundan, Anders (2012). Addiction to c-MYC in multiple myeloma. Blood. ISSN 0006-4971. 120(12), p. 2450–2453. doi: 10.1182/blood-2011-08-371567.
• Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Rampa, Christoph Samuel; Brede, Gaute & Grøseth, Lill Anny Gunnes [Show all 11 contributors for this article] (2012). Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC. Leukemia. ISSN 0887-6924. 26, p. 1073–1080. doi: 10.1038/leu.2011.263.
• Hov, Håkon; Tian, Erming; Holien, Toril; Holt, Randi Utne; Våtsveen, Thea & Fagerli, Unn-Merete [Show all 9 contributors for this article] (2009). c-Met signaling promotes IL-6-induced myeloma cell proliferation. European Journal of Haematology. ISSN 0902-4441. 82(4), p. 277–287.
• 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. Show summary

  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

• Brenne, Anne-Tove; Fagerli, Unn Merete; Shaughnessy, JD; Våtsveen, Thea Kristin; Rø, Torstein Baade & Hella, Hanne [Show all 11 contributors for this article] (2009). High expression of BCL3 in human myeloma cells is associated with increased proliferation and inferior prognosis. European Journal of Haematology. ISSN 0902-4441. 82(5), p. 354–363. doi: 10.1111/j.1600-0609.2009.01225.x.
• Hov, Håkon; Tian, Erming; Holien, Toril; Holt, Randi Utne; Våtsveen, Thea Kristin & Fagerli, Unn Merete [Show all 9 contributors for this article] (2009). c-Met signaling promotes IL-6-induced myeloma cell proliferation. European Journal of Haematology. ISSN 0902-4441. 82(4), p. 277–287. doi: 10.1111/j.1600-0609.2009.01212.x.
• 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.
• Fagerli, Unn-Merete; Holt, Randi Utne; Holien, Toril; Våtsveen, Thea Kristin; Zhan, FH & Egeberg, Kjartan Wøllo [Show all 13 contributors for this article] (2008). Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells. Blood. ISSN 0006-4971. 111, p. 806–815. doi: 10.1182/blood-2007-07-101139.

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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).
• Olsen, Oddrun Elise; Wader, Karin Fahl; Misund, Kristine; Våtsveen, Thea Kristin; Rø, Torstein Baade & Størdal, Berit Fladvad [Show all 11 contributors for this article] (2013). Membrane bound and soluble endoglin protects myeloma cells from bone morphogenetic protein 9 induced apoptosis.
• Olsen, Oddrun Elise; Wader, Karin Fahl; Misund, Kristine; Våtsveen, Thea Kristin; Rø, Torstein Baade & Størdal, Berit Fladvad [Show all 11 contributors for this article] (2013). Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin.
• Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Waage, Anders & Sundan, Anders (2013). Dependency on c-MYC in multiple myeloma.
• Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Waage, Anders & Sundan, Anders (2012). Dependency on c-MYC in multiple myeloma.
• Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Rampa, Christoph Samuel; Brede, Gaute & Grøseth, Lill Anny Gunnes [Show all 11 contributors for this article] (2011). BONE MORPHOGENETIC PROTEINS INDUCE APOPTOSIS BY SMAD-DEPENDENT DOWNREGULATION OF MYC. Haematologica. ISSN 0390-6078. 96.
• Holien, Toril; Våtsveen, Thea Kristin; Hella, Hanne; Rampa, Christoph Samuel; Brede, Gaute & Grøseth, Lill Anny Gunnes [Show all 11 contributors for this article] (2011). BONE MORPHOGENETIC PROTEINS INDUCE APOPTOSIS BY SMAD-DEPENDENT DOWNREGULATION OF MYC.
• Våtsveen, Thea Kristin; Wader, Karin Fahl; Grøseth, Lill Anny Gunnes; Sundan, Anders; Aarset, Harald & Hong Yan, Dai [Show all 8 contributors for this article] (2011). Multiple Myeloma Patients- a prospective study based on interphase-FISH on newly diagnosed patiens from 2006-2010.
• Holien, Toril; Rekvig, Magne; Våtsveen, Thea Kristin; Brenne, Anne-Tove; Rø, Torstein Baade & Waage, Anders [Show all 8 contributors for this article] (2010). Interleukins mediate protection against BMP-induced apoptosis in multiple myeloma.
• Hov, Håkon; Tian, Erming; Holien, Toril; Holt, Randi Utne; Våtsveen, Thea & Fagerli, Unn-Merete [Show all 9 contributors for this article] (2009). c-Met signaling promotes IL-6 induced myeloma cell proliferation.
• 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. Show summary

  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.

• Våtsveen, Thea Kristin (2009). Genetic chaos in myeloma cells.
• Våtsveen, Thea Kristin (2009). FISH på myelomceller fra myelompasienter i Norge.
• Våtsveen, Thea Kristin (2009). Normal B-celleutvikling som grunnlag for å forstå B-celleneoplasi.
• 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.
• 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).
• 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.
• Våtsveen, Thea Kristin; Tian, Erming; Kresse, Stine H; Meza-Zepada, Leonardo; Gabrea, Ana & Glebov, Oleg [Show all 10 contributors for this article] (2008). OH-2; a hyperdiploid myeloma cell line without an IGH translocation, has a complex translocation juxtaposing MYC near MAFB and the IGK locus.
• 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.
• Waage, Anders; Våtsveen, Thea Kristin & Aarset, Harald (2007). Cytogenetisk avvik ved myelomatose.
• Våtsveen, Thea Kristin; Engesvold, Ingeborg & Furre, Tone (2007). cIg-FISH ved cytogenetiske avvik hos myelomatosepasienter.
• Våtsveen, Thea Kristin; Dai, Hong Yan; Kresse, SH; Sundan, Anders & Børset, Magne (2007). OH-2; a human multiple myeloma cell line without IgH translocation.
• Våtsveen, Thea Kristin & Børset, Magne (2007). MiR-21 is over-expressed in cytokine stimulated multiple myeloma cell lines.
• 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.
• Våtsveen, Thea & Waage, Anders (2006). FISH analyse av myelomceller ved myelomatose.
• Våtsveen, Thea Kristin; Børset, Magne; Sundan, Anders & Waage, Anders (2009). Genetic Aberrations in Myeloma Cells. NTNU Trykk. ISSN 978-82-471-1543-5.
• 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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