Dietary Pattern and Risk of Monoclonal Gammopathy of Undetermined Significance: A Population-Based Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3257-3257
Author(s):  
Marianna Thordardottir ◽  
Ebba K Lindqvist ◽  
Sigrun H Lund ◽  
Rene Costello ◽  
Johanna E Torfadottir ◽  
...  

Abstract Background: All multiple myeloma (MM) cases are preceded by the premalignant state, monoclonal gammopathy of undetermined significance (MGUS). The etiology of MM and MGUS is to a large extent unknown. Few studies on the effect of diet on MM have been conducted and the results have been inconclusive. No studies have been conducted on the effect of diet on MGUS. Studying dietary patterns offers broader view of food consumption and possible effects of diet on diseases since many nutrients and other substances in foods act together. The aim of this study was to identify different dietary patterns at three time points throughout the lifespan and examine whether adherence to these patterns was associated with risk of MGUS and light chain MGUS (LC-MGUS) and progression to MM and other lymphoproliferative diseases. Methods: This study was based on participants from the AGES-Reykjavik Study (N=5,764; mean age 77 years). Participants gave information on frequency of intake of common foods from early life (14-19 years old), midlife (45-55 years old), and currently at study baseline (67 years and older). All participants were screened for MGUS and LC-MGUS by serum protein electrophoresis and serum free light-chain assay. We identified MM and other lymphoproliferative diseases by cross linking with the Icelandic Cancer Registry. Principal component analysis was used to extract dietary patterns. This method is data driven and forms new linear factors, (dietary patterns) by reducing data dimension and grouping correlated variables (food intake). For each pattern extracted a new variable is created, ranking participants on their adherence to that particular pattern. We used logistic regression to test association between adherence to the early life and midlife dietary patterns and MGUS and LC-MGUS, and Cox proportional hazard regression to test association between adherence to the late life patterns and progression to MM and other lymphoproliferative diseases. Results: A total of 300 (5.2%) MGUS cases and 52 (0.9%) LC-MGUS cases were identified. During 11 years of follow-up 18 cases had progressed to MM and 10 to other lymphoproliferative diseases. We extracted four dietary patterns from early life, four from midlife, and six from baseline. When analyzing MGUS and LC-MGUS cases combined we found that high adherence to pattern I from early life, the old traditional Icelandic diet (high intake of salted/smoked meat and fish, blood and liver sausage, rye bread, milk, oatmeal, and potatoes), decreased the risk (odds ratio (OR) = 0.89, 95% confidence interval (CI) 0.79-1.00), however no association was found when analyzing MGUS and LC-MGUS separately (Table 1). When analyzing midlife patterns we found that the estimate for pattern I, the old traditional Icelandic diet (high intake of salted/smoked meat and fish, blood and liver sausage, fish in salad or on bread, and meat meals) was similar to the findings from early life, although it did not reach a statistical significance (OR = 0.90, 95% CI 0.80 - 1.02). High adherence to pattern III (high intake of potatoes, whole wheat bread, milk, rye bread, and fish) from midlife decreased the risk of combined MGUS (OR = 0.88, 95% CI 0.79-0.98). When analyzing MGUS and LC-MGUS separately we found that high adherence to pattern III decreased the risk of LC-MGUS (OR = 0.69, 95% CI 0.53-0.90) but not MGUS. We did not find an association between the six patterns from late life and progression to MM. However when analyzing progression to MM and other lymphoproliferative diseases combined we found that high adherence to pattern VI (high intake of meat and milk, low intake of fish) increased the risk of progression (HR = 1.82, 95% CI 1.24-2.67). Further results can be seen in Table 1. Conclusion: Our findings suggest that high adherence to the old traditional Icelandic diet consumed during early and mid 19th century, including salted or smoked meat and fish, blood or liver sausage, rye bread, and potatoes decreases the risk of MGUS/LC-MGUS later in life. They additionally suggest an increased risk of progression to MM and other lymphoproliferative diseases, with high adherence to a pattern with high meat and low fish intake. The mechanisms for these findings are unknown but our study suggests that food intake can alter the risk of developing MGUS/LC-MGUS as well as the risk of progression to MM. Disclosures Korde: Medscape: Honoraria. Landgren:Medscape Myeloma Program: Honoraria; BMS: Honoraria; Takeda: Honoraria; Merck: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2061-2061
Author(s):  
Theodore Thomas ◽  
Su-Hsin Chang ◽  
Suhong Luo ◽  
Katiuscia O'Brian ◽  
Graham A Colditz ◽  
...  

Abstract Introduction: Multiple Myeloma (MM) is a hematologic malignancy that is universally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS). Obesity is the only known modifiable risk factor for the development of MM, though it is unclear if this is due to increased MGUS incidence or transition of MGUS to MM. In an effort to better understand how obesity may influence the progression of MGUS to MM, we analyzed patient data from the U.S. Veterans Health Administration (VHA). Methods: The VHA database was used to identify patients diagnosed with MGUS between October 1, 1999 and December 31, 2009 using ICD-9 code 273.1. Data was obtained on patient demographics, myeloma direct treatments, weight, height, and other clinical characteristics. Transition to MM was identified using two occurrences of ICD-9 code 203.0 or use of myeloma directed therapy within six months of a single use of ICD-9 code 203.0. Additionally, two investigators reviewed patient records to confirm the diagnosis and verify the diagnosis date. The World Health Organization (WHO) Body Mass Index (BMI) classification (normal-weight: 18.5≤BMI<25, overweight: 25≤BMI<30, and obese: BMI>30) was utilized to categorize BMI. Weight recorded closest to the MGUS diagnosis date was used for BMI calculations. Multivariate survival analysis (controlling for sex, race, BMI, marital status, estimated household income level, modified Charlson co-morbidity score, and creatinine level) was conducted by parametric accelerated failure time left-censored analysis with Weibull-modeled survival time. Results: There were 9,430 unique MGUS patients identified in the VHA database. Progression to MM was noted in 501 (5.3%) patients overall, with a frequency of 98/2139 (4.6%), 236/3932 (6.0%), and 167/3359 (5.0%) of the normal weight, overweight and obese BMI groups, respectively. Survival analysis revealed a statistically significant difference in progression from MGUS to MM in overweight and obese patients compared to normal-weight patients. After controlling for other variables, multivariate analysis demonstrated that obese (HR: 1.53; 95% CI 1.19-1.98) and overweight (HR: 1.45; 95% CI 1.14-1.84) patients were at increased risk of progression from MGUS to MM. Black patients (HR: 1.78; 95% CI 1.46-2.17) were also at increased risk of progression to MM. Conclusions: Patients with Monoclonal Gammopathy of Unknown Significance who are overweight or obese at the time of MGUS diagnosis are at increased risk of progression to Multiple Myeloma compared to normal weight counterparts. Also the data is suggestive that an obese BMI is associated with a higher risk of progression to MM compared to being overweight. Elevated BMI is a modifiable risk factor for progression of MGUS to MM and weight loss is a potential strategy to decrease the risk of progression. Disclosures Carson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1877-1877 ◽  
Author(s):  
Madhav V Dhodapkar ◽  
Rachael Sexton ◽  
Antje Hoering ◽  
Bart Barlogie ◽  
Robert Z. Orlowski

Abstract Introduction: Both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are associated with marked racial disparities; incidence of both MM and MGUS is increased nearly 3-fold in African American (AA) compared to Caucasian/European American (EA) cohorts. Current estimates of the risk of progression to clinical malignancy in MGUS and asymptomatic myeloma (AMM) are at 1% and 10% per year respectively, based on data from EA cohorts such as from the Olmstead county in Minnesota. Risk estimates from prospective studies in AA cohorts are urgently needed to guide optimal management of these patients. Methods: Between 2003 and 2011, 331 eligible patients with IgG/A monoclonal gammopathy were enrolled in a prospective observational trial (SWOG S0120). All patients underwent uniform staging evaluation at baseline and follow up monitoring for progression to clinical myeloma (CMM). This analysis is focused on the impact of race on clinical and biologic features and risk of progression. Results: Of 331 eligible patients, 57 (17%) were of AA descent. Clinical features of the AA cohort were comparable to the non-AA counterparts, with the exception of higher proportion of females (61% versus 43%; p=0.01) and hemoglobin < 12 g/dl (37% versus 23%; p=0.04) in the AA cohort. Among 126 patients with available data on gene expression profile (GEP) of CD138-purified plasma cells, the proportion of patients with GEP-defined subsets was similar between AA and non-AA cohorts. The risk of transformation to clinical malignancy in AA patients was significantly lower than in non-AA cohort (2 year risk 5% vs 15%; 5 year risk 13% versus 24%; log rank p 0.04). Differences in risk were evident for both MGUS (2 year risk 0% versus 2 %) and AMM (2 year risk 13% versus 25%). The proportion of patients with high risk GEP signature (GEP-70 gene risk > -0.26) in purified tumor cells was markedly lower in the AA cohort (0% versus 33%, p=0.01). Unbiased analysis of which genes in the AA cohort predict risk of progression is ongoing. Conclusions: Together these data provide the first prospective evidence that AA patients with myeloma precursor states carry significantly lower risk of progression to CMM compared to non-AA counterparts. This may be explained in part by the finding that precursor lesions in AA patients have markedly lower proportion of genomic changes (such as GEP70-risk signature derived predominantly from chromosome 1) previously associated with higher risk of malignancy in EA cohorts. The mechanisms underlying the transformation to CMM may therefore differ between AA and EA cohorts, which in turn may impact optimal management of these patients. Disclosures Barlogie: Dana Farber Cancer Institute: Other: travel stipend; Celgene: Consultancy, Research Funding; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Millenium: Consultancy, Research Funding; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Multiple Myeloma Research Foundation: Other: travel stipend. Orlowski:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Poseida: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Millenium Pharmaceuticals: Consultancy, Research Funding.


2011 ◽  
Vol 106 (8) ◽  
pp. 1253-1262 ◽  
Author(s):  
Christin Heidemann ◽  
Christa Scheidt-Nave ◽  
Almut Richter ◽  
Gert B. M. Mensink

Studies that investigated complex actual eating behaviours of the general population and their relation to cardiometabolic risk markers are sparse. We aimed to identify dietary patterns within a nationally representative sample of 4025 German adults by factor analysis based on validated dietary history interviews. Furthermore, we evaluated associations of the derived dietary patterns with abnormalities clustered within the metabolic syndrome and related metabolic markers by logistic regression models and ANCOVA. A high adherence to the ‘processed foods’ pattern reflected a high intake of refined grains, processed meat, red meat, high-sugar beverages, eggs, potatoes, beer, sweets and cakes, snacks and butter, whereas a high adherence to the ‘health-conscious’ pattern represented a high intake of vegetables, vegetable oils, legumes, fruits, fish and whole grains. For subjects in the highest compared with those in the lowest quintile of the processed foods pattern, the occurrence of abdominal obesity was 88 (95 % CI 31, 169) % higher, hypertension was 34 (95 % CI − 4, 86) % higher, hypertriacylglycerolaemia was 59 (95 % CI 11, 128 ) % higher and the metabolic syndrome was 64 (95 % CI 10, 143) % higher when adjusted for age, sex, energy intake, socio-economic status, sport activity and smoking. Furthermore, subjects in the highest quintile had statistically significantly higher uric acid concentrations and lower folate concentrations (Pfor trend < 0·05). In contrast, subjects in the highest quintile of the health-conscious pattern had a 30 (95 % CI 10, 46) % lower occurrence of hypertension, higher folate concentrations and lower homocysteine and fibrinogen concentrations (Pfor trend < 0·05). These data strengthen the findings from non-representative studies and emphasise the importance of healthy overall food patterns for preventing metabolic disturbances.


Author(s):  
Veronica Luque ◽  
Ricardo Closa-Monasterolo ◽  
Veit Grote ◽  
Gina L. Ambrosini ◽  
Marta Zaragoza-Jordana ◽  
...  

2021 ◽  
Vol 11 (6) ◽  
Author(s):  
A. Visram ◽  
C. Soof ◽  
S. V. Rajkumar ◽  
S. K. Kumar ◽  
S. Bujarski ◽  
...  

AbstractSoluble BCMA (sBCMA) levels are elevated in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, the association between sBCMA levels and prognosis in MGUS and SMM has not been studied. We retrospectively analyzed sBCMA levels in stored samples from 99 MGUS and 184 SMM patients. Baseline sBCMA levels were significantly higher in MGUS and SMM patients progressing to MM during clinical follow up. When stratified according to the median baseline sBCMA level for each cohort, higher levels were associated with a shorter PFS for MGUS (HR 3.44 comparing sBCMA ≥77 vs <77 ng/mL [95% CI 2.07–5.73, p < 0.001] and SMM (HR 2.0 comparing sBCMA ≥128 vs <128 ng/mL, 95% 1.45–2.76, p < 0.001) patients. The effect of sBCMA on PFS was similar even after adjusting for the baseline MGUS or SMM risk stratification. We evaluated paired serum samples and found that sBCMA increased significantly in MGUS and SMM patients who eventually progressed to MM, whereas among MGUS non-progressors the sBCMA level remained stable. While our results require independent validation, they suggest that sBCMA may be a useful biomarker to identify MGUS and SMM patients at increased risk of progression to MM independent of the established risk models.


Nutrients ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 898 ◽  
Author(s):  
Antonella Agodi ◽  
Andrea Maugeri ◽  
Sarka Kunzova ◽  
Ondrej Sochor ◽  
Hana Bauerova ◽  
...  

Although metabolic syndrome (MetS) could be handled by lifestyle interventions, its relationship with dietary patterns remains unclear in populations from Central Europe. Using data from the Kardiovize Brno cohort, the present study aims to identify the main dietary patterns and to evaluate their association with MetS risk in a random urban sample from Brno, Czech Republic. In a cross-sectional study of 1934 subjects aged 25–65 years (44.3% male), dietary patterns were derived by food frequency questionnaire (FFQ) administration and principal component analysis. Metabolic syndrome was defined according to the International Diabetes Federation statement. Logistic regression models were applied. High adherence to the prudent dietary pattern was associated with lower odds of abdominal obesity, abnormal glucose concentration, and MetS. By contrast, high adherence to the western dietary pattern was associated with higher odds of abnormal glucose, triglycerides and blood pressure levels. Whilst our results confirm the deleterious effect of a western dietary pattern on several metabolic risk factors, they also indicate that the consumption of a diet rich in cereals, fish, fruit and vegetables is associated with a healthier metabolic profile. However, further prospective research is warranted to develop and validate novel potential preventive strategies against MetS and its complications.


Blood ◽  
2009 ◽  
Vol 113 (22) ◽  
pp. 5412-5417 ◽  
Author(s):  
Ola Landgren ◽  
Robert A. Kyle ◽  
Ruth M. Pfeiffer ◽  
Jerry A. Katzmann ◽  
Neil E. Caporaso ◽  
...  

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77 469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)–proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-8
Author(s):  
Adam S Sperling ◽  
Rebecca Georgakopoulou ◽  
Mehmet Kemal Samur ◽  
Christine Ivy Liacos ◽  
Brittany E Sandoval ◽  
...  

Introduction: An increased inherited risk for the development of plasma cell dyscrasias (PCDs) has long been suspected, however to date, only a limited number of potential genomic risk loci have been described. To characterize the inherited risk and facilitate identification of additional risk loci it is important to combine detailed pedigrees with extensive genetic analysis. To identify familial PCDs we initiated a prospective study with active recruitment of a large cohort of patients with PCDs and active screening of their relatives combined with tissue banking and subsequent genetic analysis. Methods: All patients in the Department of Clinical Therapeutics diagnosed with PCDs between January 2017 and January 2019, were offered enrollment in the study. Following informed consent, 1st and 2nd degree relatives over the age of 30 were eligible for screening. A detailed family pedigree was created for each index case with special focus on family history of PCDs, B-cell lymphomas, or other hematologic or solid malignancies. As a control, subjects' spouses were also screened. Screening included serum protein electrophoresis with immunofixation. In families where an additional member was identified with a PCD or B-cell malignancy, peripheral blood was collected from consenting family members over the age of 18 for further genetic analysis. Samples from affected individuals were profiled using whole genome sequencing (WGS) and unaffected individuals were genotyped using Axiom Arrays. Data were analyzed using Axion Array Suite and plink and GATK toolkit with BWA. Results: Of 1,084 patients screened for participation in the study; 752 had multiple myeloma (MM), 77 had smoldering MM, 81 a monoclonal gammopathy of undetermined significance, 93 Waldenström's Macroglobulinemia and 81 had AL amyloidosis. 176 (16.2%) patients refused to participate in the study, while 44 (4.1%) patients were ineligible for further screening due to the absence of a living first- or second-degree relative. The median number of screened first or second-degree relatives per index patient was 3 (range 1 to 10). The median age of index cases was 65 years, offspring was 37 years, second-degree relatives was 65 years, and spouses was 65 years. The incidence of a PCD among second-degree relatives was 4.5%, while it was 0.6% among offspring. As a control group, the incidence of PCDs among spouses was 2.6%. Overall at least one additional member (beyond the index patient) with a monoclonal gammopathy was detected in 98 families (11.3%). In 57 families (6.6%) there was a positive history of at least one additional first- or second-degree relative with a PCD or B-cell malignancy. In addition, 41 new cases of monoclonal gammopathy (4.7%) were identified through the screening process associated with this study. To identify genetic loci that could be associated with a predisposition to development of PCDs, genetic analysis was performed on the most heavily affected 18 families, those with at least three affected members or with early onset disease (i.e. PCD diagnosed before age 50). We have evaluated 838,750 SNPs from 103 samples from 18 families. 30 samples were from affected members and 73 from unaffected members. We found eight SNPs (rs13233413, rs11648113, rs59444635, rs148480125, rs113556240, rs11547122, rs671880, rs4726610) that are significantly enriched in affected members with a p-value below the suggestive cut-off of &lt;1e-5. The top candidate was in the untranslated region (UTR) of TSPAN33, a marker of activated and malignant B-cells. We did not detect any significant enrichment in germline mutations in previously reported genes associated with familial PCD risk such as KDM1a, KRAS or DIS3. Functional annotation of the 8 SNPs identified here showed that rs148480125, located in the promoter region of the apoptosis regulator SIVA1, is predicted to impact the allele specific expression level. Further validation work is ongoing. Conclusions: Our active prospective screening approach to identify familial predisposition to PCDs revealed that 11.3% of patients had families with at least one additional affected member and some families had a substantially higher incidence of PCDs with earlier onset. Study of these high-risk families have identified genomewide association markers which in future may help us define familial predisposition to plasma cell dyscrasias. Disclosures Gavriatopoulou: Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria. Munshi:Janssen: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; C4: Current equity holder in private company; Adaptive: Consultancy. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Takuro Kameda ◽  
Kotaro Shide ◽  
Ayako Kamiunten ◽  
Tahira Yuki ◽  
Masaaki Sekine ◽  
...  

Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma that develops in about 5% of human T-cell leukemia/lymphoma virus 1 (HTLV-1) carriers. In addition to viral oncogenes, namely tax and HTLV-1 bZIP factor (HBZ), gene mutations, highly enriched for T-cell receptor (TCR)-NF-kB signaling, should be involved in the development of ATL. Among gene mutations, mutation in CARD11, a cytoplasmic scaffolding protein required for TCR-induced NF-kB activation, was detected in 24% of ATL patients. Here we generated a mouse model for conditional expression of a human ATL-derived CARD11(E626K) gain-of-function mutant, and demonstrated CARD11 activation induced oligoclonal expansion of T-cell and infiltration to many organs. We also showed that expression of HBZ accelerated mutant CARD11-induced lymphoproliferative diseases. We introduced a human Card11(E626K) into the mouse genome at the ROSA26 locus. After crossing with CD4-Cre Tg, CARD11(E626K)CD4-Cre mice was obtained. In CD4+ cells from CARD11(E626K)CD4-Cre, the amount of cleaved BCL-10 and NF-kBp65 increased compared with those in WT CD4+cells, confirming the activation of NF-kB. About half of CARD11(E626K)CD4-Cre mice died on or after 6 months after birth. At 6 months, leukocytosis was observed in CARD11(E626K)CD4-Cre, and accordingly the number of CD4+ cells cells was about 1.43 times greater than those in WT mice. The most affected organ in CARD11(E626K)CD4-Cre mice was lung. Alveolar septum was thickened by infiltrated cells at 6 months, and worsened subsequently. CD3+ T-cell accumulated around capillary blood vessels, and had high proliferation indices (&gt;50%), as assayed by Ki-67 staining. CARD11(E626K)CD4-Cre mice developed lymphadenopathy (4/8 mice (50%) at 6M and 4/6 mice (66.7%) at 12M). Normal lymph node (LN) architecture was barely preserved, and medullary sinus was expanded with CD3+ T-cell. Some of them were positive for FoxP3, and had moderate proliferation indices (25%-50%). Among CD4+ T-cell, the proportion of naive T-cell (Tn) decreased, and that of effector/memory T-cell (Tem) and regulatory T-cell (Treg) increased compared to WT LNs. The proportion of Treg in CD4+ T-cell from LN of 6M- and 12M-old CARD11(E626K)CD4-Cre mice was 25% and 40%, respectively, which values were much larger than the normal range as 10-15%. We next examined the clonality of CD4+ cells in spleen and swollen LNs from CARD11(E626K)CD4-Cre mice. The clonality of the TCR repertoires of 20 individual Vb gene famines from Vb1-20 was assessed by a PCR. The clonality assay using the TCR repertoires exhibited an oligoclonal pattern in 4 of 5 splenic CD4+ cells, and 1 of 2 LN CD4+ cells from CARD11(E626K)CD4-Cre mice. To assess the effect of HBZ constant expression on CARD11(E626K)CD4-Cre mice, we generated HBZ Tg, in which HBZ cDNA was expressed under the CD4 promoter. Similar to the previous report (by Satou et al.), our HBZ Tg showed increased number of Tem, destroyed architecture of lung such as thickened alveolar septum by infiltrated cells and decreased alveolar space by edema, and the lymphadenopathy after 12M (66.7%). We then crossed CARD11(E626K)CD4-Creand HBZ Tg, and obtained the compound mice. The compound mice caused more aggressive lymphoproliferative diseases compared with CARD11(E626K)CD4-Cre mice. Most of compound mice died within 8M. At 6M, architecture of lung, kidney, spleen, and LN was destroyed. In lung, alveolar space of lung was scarcely observed caused of T-cell invasion. Alveolar septum was thickened with infiltrated cells, and CD3+ cells accumulated around capillary blood vessel. Some of them were positive for FoxP3, and indicated moderate proliferation indices (25-50%). T-cell invasion was also observed in kidney. Lymphadenopathy was detected in 6 of 9 (66.7%) with completely destroyed architecture, increment of the proportion of Fox3+ cells, and moderate proliferation indices (25-50%). The clonality assay using the TCR repertoires exhibited an oligoclonal pattern in 4 of 4 splenic CD4+ cells, and 2 of 2 LNs CD4+ cells from compound mice. These results suggest that CARD11 mutant-induced NFkB activation and constant HBZ expression may have similar effects, such as T-cell infiltration into organs and LN adenopathy, and that the simultaneous occurrence of both may have additive effects. Disclosures Sugiyama: Chordia Therapeutics, Japan.: Current Employment. Morishita:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company. Shimoda:Perseus Proteomics: Research Funding; PharmaEssentia Japan: Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma: Research Funding; Merck & Co.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding; Celgene: Honoraria; Shire plc: Honoraria; Novartis: Honoraria, Research Funding; Takeda Pharmaceutical Company: Honoraria; Bristol-Myers Squibb: Honoraria.


2018 ◽  
Vol 58 (4) ◽  
pp. 1495-1505 ◽  
Author(s):  
Adela Castelló ◽  
◽  
Pilar Amiano ◽  
Nerea Fernández de Larrea ◽  
Vicente Martín ◽  
...  

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