Multiple Myeloma Sequencing Reveals Subclonality and Timing of Genetic Alterations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2897-2897
Author(s):  
Jens Lohr ◽  
Petar Stojanov ◽  
Michael S Lawrence ◽  
Daniel Auclair ◽  
Scott Carter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Time Course ◽  
Somatic Mutations ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Classification Systems ◽  
Driver Mutations ◽  
Kras Mutations

Abstract Abstract 2897 Multiple myeloma is considered to be a homogenous disease within a given patient, and current classification systems and treatment algorithms are based on this assumption. We have asked if there is genetic heterogeneity of multiple myeloma within a patient and if this heterogeneity can be quantified. To address this question, we have used massively parallel whole exome and whole genome sequencing of tumors and matched normal controls of 64 patients with multiple myeloma. We present an analytic strategy to distinguish potential driver mutations based on their clonality. We demonstrate that in some patients there are many somatic mutations that are only present in a subclonal fraction of the malignant plasma cells, and the subclonal fraction comprises up to 50%. These mutations are therefore less likely to confer a selective clonal advantage and are less attractive therapeutic targets because they only affect a small fraction of the myeloma cells. As an example, we found KRAS to be one of the most prevalent mutated genes in multiple myeloma, and KRAS mutations are significantly more likely clonal than subclonal, while other mutations in other genes are predominantly subclonal. We also used this approach to investigate how copy number variations are related to somatic mutations, i.e. to define the temporal sequence of these events. This question is particularly relevant for hyperdiploidy in multiple myeloma, since this is associated with trisomies of odd numbered chromosomes. However, these trisomies do not occur with the same frequency in all odd numbered chromosomes and some hyperdiploid samples are also associated with trisomies of various even numbered chromosomes. It is unclear if these trisomies occur as a single catastrophic event, or rather in a sequential fashion. By assuming a constant rate of somatic mutations and utilizing this rate as a “timer” for chromosomal duplications we demonstrate that trisomies of odd-numbered chromosomes appear to occur early in a distinct order, whereas trisomies of even-numbered chromosomes and chromosome 1q occur late. Our analyses allow us to determine which somatic mutations occurred before chromosomal duplication and may therefore give insight in the time course of pathogenic genetic alterations in multiple myeloma. Our work may also play an important role in prioritizing somatic mutations for therapeutic targeting in multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

Uncovering Clonal and Subclonal Druggable Targets in Multiple Myeloma Using Omic Data

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2084-2084
Author(s):  
Adam David Scott ◽  
Venkata D Yellapantula ◽  
Christopher J Yoon ◽  
Michael Wendl ◽  
Michael H. Tomasson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Drug Targets ◽  
Time Course ◽  
Somatic Mutations ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Analysis Tool ◽  
Precision Oncology ◽  
Cancer Types

Abstract The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial is the keystone program working towards personalized medicine in multiple myeloma (MM). CoMMpass has characterized over 730 samples from 669 patients, a subset having time-course data, using multiple platforms and has made these data publicly available. Screening for druggable somatic mutations and gene expression outliers revealed great potential for repurposing existing pharmacotherapies. We have developed and curated a Database of Evidence for Precision Oncology (DEPO) that includes 442 mutations and 49 genes with expression changes implicated as drug targets from 34 cancer types. We found 43.6% of CoMMpass samples have one of 26 somatic mutations that could be targeted by 9 different drugs, suggesting many drugs may be repurposed for use in MM. HotSpot3D, a protein-structure-guided analysis tool, showed 3.3% (24/730) of samples have mutations involving BRAF and KRAS, clustering with known drug targets, and another 2.1%(15/730) have mutations in clusters formed from a prior TCGA pan-cancer analysis involving 22 cancer types. This indicates additional potential drug targets and functional mutations in MM. Interestingly, 11 samples (including relapse), have subclonal mutations in both KRAS and BRAF with variable allelic fractions, implicating different treatment requirements for tumor subpopulations and disease stages. Additionally, druggable gene expression outlier analysis of 591 samples reveals an average of nearly 5 outlier genes per sample from among 49 known target genes, with 18.1% (107/591) of samples with MYCN gene outliers as compared to MYC 1.4% (8/591), despite MYC being a known driver of MM. Other top outliers are DLL3 10.2%, EGFR 10.5%, FGFR1 10.2%, and FGFR2 12.5%. Our study highlights candidate drug targets previously omitted in MM. Taken together, it suggests that heterogeneity analysis and pharmaceutical repurposing could lead to substantially improved outcomes. Disclosures No relevant conflicts of interest to declare.

scholarly journals Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

2013 ◽  
Vol 98 (2) ◽  
pp. E364-E369 ◽  
Author(s):  
Nishant Agrawal ◽  
Yuchen Jiao ◽  
Mark Sausen ◽  
Rebecca Leary ◽  
Chetan Bettegowda ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Somatic Mutations ◽  
Medullary Thyroid Cancer ◽  
Driver Mutations ◽  
High Confidence ◽  
Kras Mutations ◽  
Protein Coding ◽  
Medullary Thyroid ◽  
Oncogenic Mutations ◽  
Independent Cohort

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

Genetic Alterations in Chinese Resected Lung Cancer with Invasive Mucinous Adenocarcinoma: Genomic Profiling and Prognostic Value Analysis

2021 ◽  
Author(s):  
James D. Klingensmith
Keyword(s):  
Mucinous Adenocarcinoma ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Kras Mutations ◽  
Genetic Characteristics ◽  
Value Analysis ◽  
Invasive Mucinous Adenocarcinoma

Lung invasive mucinous adenocarcinoma (IMA) is a unique histological subtype with different clinical and pathological characteristics. Despite prior genomic investigations on lung IMA, little is known about the genetic features and prognosis-related biomarkers in Chinese surgically resected lung IMA. IMA showed a distinct genetic profile, with more diversified driver mutations and co-occurrence of tumor drivers/suppressors than non-IMA. From non-IMA to mixed-IMA to pure-IMA, the frequency of EGFR (72.0 percent vs. 40.0 percent vs. 23.1 percent, p=0.002) and ALK (undetected vs. 20.0 percent vs. 26.9%, p=0.015) changes exhibited a trend of steady decline and rise, respectively. KRAS mutations were more common in pure-IMA than in mixed-IMA, however the difference was statistically insignificant (23.1 percent vs. 4.0 percent, p=0.10). Pure-IMA had a lower rate of TP53 mutation than mixed-IMA and non-IMA (23.1 percent vs. 52.0 percent vs. 56.0 percent, p=0.03). Furthermore, IMA had fewer arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, with a steady drop in amplification and rise in deletion frequency from non-IMA to mixed-IMA to pure-IMA, respectively. Patients with EGFR mutations (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway mutations (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) had longer DFS than patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or KRAS mutations (mDFS=13 KRAS mutations, PI3K pathway changes, and tumor differentiation status were all shown to be independent predictors with statistically significant effects on IMA patients' clinical outcomes in multivariate analysis. Our research shed light on the genomics of Chinese lung IMA that had been surgically removed. In IMA patients with stage III illness, we also discovered many genetic characteristics that might be used as indicators for postoperative recurrence.

scholarly journals Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma

2020 ◽  
Vol 4 (22) ◽  
pp. 5616-5630
Author(s):  
Tiziana Bruno ◽  
Francesca De Nicola ◽  
Giacomo Corleone ◽  
Valeria Catena ◽  
Frauke Goeman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rna Polymerase Ii ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Global Gene Expression ◽  
Clonal Expansion ◽  
Genetic Alterations ◽  
Active Chromatin ◽  
Promising Target ◽  
External Domain

Abstract Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che-1 depletion leads to a reduction of “active chromatin” by inducing a global decrease of histone acetylation. In this context, Che-1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che-1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.

Obesity is Associated with a 2-Fold Elevated Risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) Among African-American and Caucasian Women.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4876-4876
Author(s):  
Ola Landgren ◽  
Vincent Rajkumar ◽  
Ruth Pfeiffer ◽  
Robert Kyle ◽  
Jerry Katzmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African American ◽  
African Americans ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Pearson Correlation ◽  
Elevated Risk ◽  
Caucasian Women ◽  
Undetermined Significance

Abstract Abstract 4876 Background Recent studies have found obesity to be associated with a 1.5- to 2-fold elevated risk of developing multiple myeloma. This is of particular interest given that elevated levels of the pro-inflammatory cytokine interleukin (IL)-6 have been found in obese persons, and, at the same time, IL-6 has well-known proliferative and anti-apoptotic effects on monoclonal plasma-cells. Also insulin-like growth factors (IGFs) have been proposed to play a role since obesity often causes insulin resistance, which in turn modulates the bioavailability of IGF-1 Similar to IL-6, prior studies have found IGF-1 to have both growth and survival effects on monoclonal plasma-cells. Based on these facts, we have speculated that obesity might increase the risk of the multiple myeloma precursor monoclonal gammopathy of undetermined significance (MGUS), or, alternatively, that obesity may increase the risk for transformation from MGUS to multiple myeloma. We conducted the first large screening study designed to assess the association between obesity and MGUS among almost 2,000 African-American and Caucasian women. Methods We included 1000 African-American and 996 Caucasian women (age 40-79, median 48 years) from the Southern Community Cohort Study to assess MGUS risk in relation to obesity. Per our sampling strategy, about 50% of the participants were obese. Medical record-abstracted weight and height (measured on the day of study enrollment) and self-reported values had very high concordance (Pearson correlation >0.95). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Using logistic regression models, we estimated odds ratios (ORs) as measures of risk. Results Among all study participants, 39 (3.9%) African-Americans and 21 (2.1%) Caucasians were found to have MGUS, yielding a 1.9-fold (95%CI 1.1-2.3; p=0.021) higher risk of MGUS among African-Americans (vs. Caucasians). On multivariate analysis, we found obesity (OR=1.8, 95%CI 1.03-3.1; p=0.039), African-American race (OR=1.8, 95%CI 1.04-3.1; p=0.037), and increasing age (quartiles: ≥55 vs. <43 years) (OR=2.5, 95%CI 1.1-5.7; p=0.028) to be independently associated with an excess risk of MGUS. Another interesting finding was that the distribution of the monoclonal immunoglobulin isotype usage among African-American and Caucasian women was significantly different (p=0.007). Their respective rates were: IgG in 79.5% and 71.3 %; IgA in 7.7% and 0%; IgM in 7.7% and 19%; biclonal in 5.1% and 4.7%; and triclonal in 0% and 4.7%. The distribution of serum light-chain types between the two races was also significantly different (P=0.003, chi-square test): kappa in 53.8% and 47.6%; lambda in 43.6% and 42.8%; biclonal 2.6% and 4.7%; and triclonal in 0% and 4.7%. Conclusions Our finding that MGUS is twice as common among obese (vs. non-obese) women, and independent of race, supports the hypothesis that obesity is etiologically linked to myelomagenesis and may have public health impact. The observed 2-fold excess of MGUS among African-Americans (vs. Caucasians) of similar socio-economic status, coupled with other recent studies supports a role for susceptibility genes as the cause for racial disparity in the prevalence of MGUS. Disclosures No relevant conflicts of interest to declare.

Serum/Glucocorticoid-Regulated Kinase 1 (SGK1) Is a Prominent Target Gene of the Transcriptional Response to Cytokines In Multiple Myeloma and Supports the Growth of Myeloma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1915-1915
Author(s):  
Unn-Merete Fagerli ◽  
Thorsten Stühmer ◽  
Toril Holien ◽  
Randi Utne Holt ◽  
Ove Bruland ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factors ◽  
Cell Lines ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Transcriptional Response ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Growth And Survival ◽  
Stat3 Phosphorylation

Abstract Abstract 1915 Multiple myeloma is a paradigm for a malignant disease that exploits external stimuli of the microenvironment for growth and survival. A thorough understanding of the complex interactions between malignant plasma cells and their surrounding requires a detailed analysis of the transcriptional response of myeloma cells to environmental signals. We hypothesized that the intracellular signals evoked by cytokines converge and regulate transcription of a set of genes that are common targets for several growth factors and therefore constitute pivotal mediators of the tumor-promoting effects of autocrine or paracrine stimuli. To identify such targets, we determined the changes in gene expression induced by IL-6, TNFalpha, IL-21 or co-culture with bone marrow stromal cells in myeloma cell lines. Among a limited set of genes that were consistently activated in response to growth factors, a prominent transcriptional target of cytokine-induced signaling in myeloma cells was the gene encoding the serine/threonine kinase SGK1, which is a down-stream effector of PI3-kinase and highly homologous to AKT. We could demonstrate a rapid, strong and sustained induction of SGK1 in the cell lines INA-6, ANBL-6, IH-1, OH-2 and MM.1S as well as in primary myeloma cells. Pharmacologic inhibition of the JAK/STAT pathway abolished STAT3 phosphorylation and SGK1 induction. In addition, shRNA-mediated knock-down of STAT3 reduced basal and induced SGK1 levels, demonstrating the involvement of the JAK/STAT3 signaling pathway in SGK1 induction. Furthermore, down-regulation of SGK1 by shRNAs resulted in decreased proliferation and viability of myeloma cell lines. Our results indicate that SGK1 is a highly cytokine-responsive gene in myeloma cells promoting their growth and survival and represents an attractive candidate for further evaluation as a therapeutic target. Disclosures: No relevant conflicts of interest to declare.

IDH1 and IDH2 mutations are Not Frequent In Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4992-4992 ◽  
Author(s):  
Christian Langer ◽  
Mariam Ibañez ◽  
Peter Liebisch ◽  
Thorsten Zenz ◽  
Stefan Knop ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Performance ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Rare Event ◽  
Gene Mutations ◽  
Isocitrate Dehydrogenase 1 ◽  
Aberrant Expression ◽  
Genetic Abnormalities ◽  
Idh1 And Idh2 Mutations

Abstract Abstract 4992 Multiple myeloma (MM) is characterized by frequent and complex genomic abnormalities. However, most genetic abnormalities are already present in the precursor state of MM, the monoclonal gammopathy of undetermined significance (MGUS). Therefore, it is likely that secondary genetic events might contribute to the development from MGUS to symptomatic MM. Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes have recently been described as relatively frequent molecular lesions in gliomas and in acute myeloid leukemia (AML). However no larger study has so far examined the frequency of IDH1 and IDH2 gene mutations in patients (pts) with MM. Methods: In 188 pts with MM genomic DNA from CD138 sorted plasma cells was used for analyses. Exon 4 of both IDH1 and IDH2 were amplified by PCR and the amplicons were analyzed using a combination of denaturing high-performance liquid chromatography and DNA sequencing. All patients were also characterized by a comprehensive set of FISH probes for the presence of recurring cytogenetic abnormalities. Results: 185 out of 188 samples were evaluable for analyses. One missense mutation in the IDH2 gene (c.G419A) was identified in the cohort of 185 MM pts (0.5%). This mutation was described as the most frequent IDH2 mutation in AML and is predicted to cause an amino acid change from arginine to glutamin at position 140 (p.R140Q). On cytogenetic analysis this patient harbored a translocation t(11;14) resulting in aberrant expression of CCND1. Additionally, in 15 pts (8%) the recently described single nucleotide polymorphism (SNP) in the IDH1 gene (rs11554137) was detected that has been reported as an adverse prognostic factor in cytogenetically normal AML. Summary: Mutations in the IDH1/2 genes are a rare event in MM (0.5%). Further studies are warranted to address the issue if IDH1/2 mutations are restricted to distinct genetic subgroups as for example the group of MM pts with translocation t(11;14). Disclosures: No relevant conflicts of interest to declare.

Coexistance of Multiple Myeloma and Myelodysplastic Syndrome or Lymphoid Diseases At Diagnosis: Evidence for Two Clonal and Independent Chromose Abnormalities

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5063-5063
Author(s):  
Hossein Mossafa ◽  
Sabine Defasque ◽  
Christine Fourcade ◽  
JeanPierre Hurst ◽  
Bertrand Joly
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Chromosome 8 ◽  
Trisomy 8 ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Trisomy 12

Abstract Abstract 5063 Introduction, We describe the simultaneous presentation of multiple myeloma (MM) and yeloproliferative disorders (MPD) or lymphoid diseases (LD) at diagnosis. Therapy-related myelodysplasia (tMDS) occurring during the course of MM is generally believed as a result from hematopoietic stem cell-toxic therapies, such as ionizing radiation and alkylating agent-based chemotherapies (melphalan, nitrosoureas).Patients and methods, We study a total of 342 patients (151 F, 191 M; median age 68.1 years; range 42 to 93 Years), diagnosed with MM based on the International Staging System. The basis for inclusion of patients in this study was with previous untreated MM ones. The study was performed in accordance with the declaration of Helsinki. To determine whether chemotherapies for MM factors play the critical role in the development of secondary disease, simultaneously two different cultures were processed, an unstimulated 96 hours culture (U96HC) on whole BM(WBM), a short-time 24 hours culture (ST24HC) after CD138+ plasma cells (PCs) depleted on negative fraction (CD138- cells) of BM and the FISH was investigated on purified CD138+.All samples were enriched in PCs by the Automated Magnetic Cell Sorter (Miltenyi technology)proceeded with anti-CD138 specific antibodies applied. The CD138+ PCs and the CD138- cells were collected in different tubes. The CD138− cells were used for a ST24HC. FISH was performed on the purified CD138+, PCs with a recommended FISH panel (MM International Working Group). Screening was performed systematically for the following unbalanced alterations and reciprocal rearrangements: del(13)(q14)(D13S25), del(17)(p13)(TP53),+3(D3Z), +9(D9Z1), +15(D15Z14), t(4;14)(p16;q32)/IGH-FGFR3, t(11;14)(q13;q32)/IGH-CCND1 (Abbott).After observing the results of U96HC on whole BM (CD138+ and CD138− cells), ST24HC (CD138− cells) and FISH for each patient, two clone cytogenetically were distinct and unrelated chromosomal abnormalities were found in 40 (11.7%) of the 342 MM patients (6 F, 34 M; median age 74 years; range 42 to 87 Years) 34 had a MPD and 6 had a LD. A second immunophenotyping analysis confirmed the presence of those LD/MM simultaneous haematological malignancy. In the cases of the patients with MM/ MPD, the frequency of cytogenetic abnormality unrelated to the myeloma clone was respectively; the 20q deletion, detected for 13 the 34 patients, the 20q- is a sole abnormality for 12 cases and associated with a complex caryotype in 1 case. The trisomy of chromosome +8 was observed in 7 cases, the del(7q) or monosomy 7 in 5 cases, loss of gonosome Y in 4 cases, del(11) for 2 cases, translocation t(9;22) in one case, 5q abnormality in one case and trisomy 9 with JAK2 V617F mutation in one case. For the patients with MM/LD, 5 patients had a trisomy +12 and or trisomy +18 like sole abnormality or associated with others cytogenetics abnormalities and one patient had 6q deletion. Discussion, Whereas in the literature the most common cytogenetic abnormalities typifying MPD after alkylator-based therapy include partial or complete deletions of chromosomes 5, 7, and 20 as well as trisomy 8. In our study we observed those abnormalities with the same frequency for the patients had simultaneous MPD associated in untreated MM at diagnosis. Six patients had simultaneous LD and MM. The marginal zone lymphoma was confirmed for 3 patients. The CC observed a trisomy +12 for those three patients associated with +18 and +19 for 2 cases and del(13) and trisomy 3 for one among them. We demonstrated in untreated MM patients the coexistence of MM and MPD or LD at diagnosis with MPD-type or LD-type chromosome abnormalities within MM signature karyotype. We hence recommend that CC studies, 96 hours WBM, 24 hours on negative fraction CD138− cells and FISH on purified CD138+ PCs, the three should be an integral part of the evaluation of patients with MM at diagnosis into clinical trials using HDT is warranted to determine whether patients who are predisposed to developing tMDS/sAML, they can be identified prospectively. Disclosures: No relevant conflicts of interest to declare.

Membrane Lipid Biosynthesis As a Potential Therapeutic Target in Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1836-1836
Author(s):  
Carolyne Bardeleben ◽  
Alan Lichtenstein
Keyword(s):  
Multiple Myeloma ◽  
Er Stress ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Membrane Lipid ◽  
Dependent Manner ◽  
Kennedy Pathway ◽  
Phosphatidylcholine Synthesis

Abstract Abstract 1836 Phosphatidylcholine (PC) is the most prominent phospholipid in mammalian endoplasmic reticulum (ER) membranes. The rate-limiting step in PC synthesis through the Kennedy pathway is the conversion of phosphocholine + cytidine triphosphate (CTP) to cytidine diphosphocholine, (CDP)-choline, via the enzyme CTP:phosphocholine cytidylyltransferase (CCT) (see figure). Multiple myeloma (MM) cells may be particularly dependent on this biosynthetic reaction because of their high consistent level of ER stress and requirement to continuously replenish ER membranes. Indeed, CCT-null mice have a defect in differentiation of B lymphocytes to plasma cells and deficiencies in Ig synthesis. To test whether this pathway remains critical in survival of malignant MM cells, we exposed MM cell lines to an inhibitor shown to inhibit CCT activity, HexPC. HexPC induced apoptosis in all MM cell lines in a concentration- and time-dependent manner. The addition of lysophosphatidylcholine (LPC), presumably converted to PC independently of the Kennedy pathway, completely rescued MM cell apoptosis. In contrast, similar concentrations of LPC in the same cell lines could not rescue apoptosis induced by bortezomib. An additional intervention to inhibit phosphatidylcholine synthesis, namely inducing pyrimidine starvation, also resulted in MM cell apoptosis and down-regulation of CDP-choline levels. Apoptosis of MM cells induced by HexPC was associated with induction of ER stress as shown by enhanced phosphorylation of IRE1 and eIF-2alpha. This ER stress was also prevented when LPC was added to HexPC although LPC could not prevent similar ER stress induced by bortezomib. These results underscore the importance of this phosphatidylcholine synthesis pathway in MM cells and provide new targets for future therapy. Disclosures: No relevant conflicts of interest to declare.

Metabolomics Identifies Potential Biomarkers of Multiple Myeloma Development and Progression

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3985-3985
Author(s):  
Francesca Fontana ◽  
Josè Manuel garcia Manteiga ◽  
Magda Marcatti ◽  
Francesca Lorentino ◽  
Giovanni Tonon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
In Vitro Tests ◽  
Incurable Cancer ◽  
Disease Evolution ◽  
Cell Counts ◽  
Bone Marrow Plasma ◽  
Active Disease

Abstract Abstract 3985 Multiple myeloma is a malignancy of plasma cells, which grows at multiple foci in the bone marrow, secretes monoclonal immunoglobulins, and typically induces skeletal destruction, hypercalcemia, anemia, and renal failure. Although it remains an incurable cancer, novel therapeutic regimens have improved overall survival in the last decade. Multiple myeloma originates from post germinal center, terminally differentiated B lymphocytes through a multi-step process involving early and late genetic changes. Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS), a frequent age-progressive premalignant expansion of bone marrow plasma cells that behave benignly despite the presence of most myeloma-specific genetic abnormalities. Indeed, development and progression of multiple myeloma are believed to rely on vicious interactions with the bone marrow environment, offering a paradigm to investigate the bone-cancer relationship. In particular, bone and stromal cells are known to be diverted by cancer cells through altered cytokine circuitry. The resulting enhanced osteoclastogenesis and neoangiogenesis, and reduced osteoblast differentiation and activity sustain cancer cell survival, proliferation, migration and chemoresistance. Such crucial interactions, however, have only partially been elucidated in their complexity, dynamics and exact role in disease evolution. A better knowledge of this interplay, still elusive, could help identify prognostic markers, pathomechanisms, and therapeutic targets for future validation. Aiming to achieve an unbiased, comprehensive assessment of the extracellular milieu during multiple myeloma genesis and progression, we performed a metabolomic analysis of patient-derived peripheral and bone marrow plasma by ultra high performance liquid and gas chromatography followed by mass spectrometry. By feature transformation-based multivariate analyses, metabolic profiling of both peripheral and bone marrow plasma successfully discriminated active disease from control conditions (health, MGUS or remission). Moreover, both central and peripheral metabolic scores significantly correlated with bone marrow plasma cell counts. Significant changes in the peripheral metabolome were found to be associated with abnormal renal function in the subset of myeloma patients. Noteworthy, however, renal dysfunction-associated features failed to independently predict disease load, while non-overlapping disease vs. control analyses consistently identified a number of metabolites associated with disease. Among these, increased levels of the C3f-derived peptide, HWESASLL, and loss of circulating lysophosphocholines emerged as hallmarks of active disease. In vitro tests on myeloma cell lines and primary patient-derived cells revealed a previously unsuspected direct trophic role exerted by lysophosphocholines on malignant plasma cells. Altogether, our data demonstrate that metabolomics is a powerful approach suitable for studying the complex interactions of multiple myeloma with the bone marrow environment and general metabolism. This novel strategy holds potential to identify unanticipated markers and pathways involved in development and progression of multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

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