Whole-Genome Sequencing Results From 30 Patients with Waldenstrom's Macroglobulinemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 434-434 ◽  
Author(s):  
Zachary Hunter ◽  
Lian Xu ◽  
Yangsheng Zhou ◽  
Guang Yang ◽  
Xia Liu ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Whole Genome ◽  
Waldenström’S Macroglobulinemia ◽  
Complete Genomics ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 434 Introduction: The primary oncogenetic event resulting in malignant transformation in Waldenstrom's Macroglobulinemia (WM) remains to be delineated. We therefore employed whole genome sequencing (WGS) to help identify potential somatic variants in WM. Patients and Methods: Thirty patients meeting consensus criteria for the diagnosis of WM were included for these studies, whose characteristics are depicted in Table 1. CD19-magnetic bead sorting was used for isolation of bone marrow LPC. CD19-depleted PB mononuclear cells were collected as matched normal tissue. For 10 patients, WGS of tumor and matched normal samples was performed, and for 20 additional patients tumor samples alone were completely sequenced. Library construction and WGS was performed by Complete Genomics Inc. Read sequences were aligned to the NCBI Build 37. High confidence somatic variants were identified using cgatools version 1.3. Novel non-synonymous exonic variants for familial and sporadic LPL/WM patients were identified using ANNOVAR using to filter against several large databases including dbSNP version 132, the November 2010 release version of the 1,000 genomes project, and a 46 healthy donor dataset from Complete Genomics, Inc. based on KnownGene annotations. Variants filtered out in this process were checked against the dbSNP132 flagged SNP database for potential clinical significance. Data was further annotated against the Database of Genomic Variants and the Segmental Duplication Database, TargetScan, and transcription factor binding site data from the ENCODE project. When applicable, variants were scored using SIFT, PolyPhen2 and Mutation Taster. Copy number neutral loss of heterozygosity (CNLOH) was identified from the rate of heterozygous variants per 500,000 base pairs, CG content adjusted coverage data, and allele imbalance calculated from the percentage of total reads supporting the less covered allele. Results: Tumor and normal genomes were both sequenced to an average of 66X (range 60–91X) coverage of mapped individual reads. The average gross mapped yield for these genomes was 186.89 (range 171.56–262.03 Gb). Acquired copy number changes were common, and included losses in chromosome 6q (13/30; 43%), gains in chromosome 4 (7/30; 23%), and gains in 6p (3/30; 10%). Large regions of CNLOH were observed in 9/30 (30%) of patients occurring in chromosomes 1, 2, 3, 5, 9, 11, 17, 21, and X. The most frequent somatic variant occurred at position 38182641 in chromosome 3p22.2 in the myeloid differentiation primary response (MYD88) gene, resulting in a non-synonymous change at amino acid position 265 from leucine to proline (L265P) in 26/30 (86.7%) patients. Of these, 4/26 (15%) had a CNLOH covering this position making the variant effectively homozygous. Additional somatic variants occurred in transporter 2, ATP-binding cassette, sub-family B (TAP2) gene in 7/30 (23%) patients; chemokine (C-X-C motif) receptor 4 (CXCR4) gene in 6/30 (20%) patients. Somatic variants were also identified in the coding regions of low density lipoprotein receptor-related protein 1B (LRP1B) gene in 5/30 (17%) patients; mesothelin (MSLN) gene in 4/30 (13%) patients; AT rich interactive domain 1A (ARID1A) gene in 3/30 (10%) patients; histone cluster 1, H1e (HIST1H1E) in 3/30 (10%) patients, and Rap guanine nucleotide exchange factor 3 (RAPGEF3) in 3/30 (10%) patients. Conclusions: The results of this study provide the first reporting of comprehensive WGS efforts in patients with WM, and reveal recurring somatic variants in genes with important regulatory functions including MYD88, TAP2, and CXCR4. Structural and functional validation studies are ongoing and will be updated at the meeting. The results of these studies provide important new insights into the pathogenesis of WM. Disclosures: No relevant conflicts of interest to declare.

Highly Recurrent Copy Number Alterations and Insight Into The Origins Of 6q Deletions In Waldenström’s Macroglobulinemia Revealed By Whole Genome Sequencing

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4254-4254
Author(s):  
Zachary Hunter ◽  
Lian Xu ◽  
Guang Yang ◽  
Xia Liu ◽  
Yang Cao ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Statistical Significance ◽  
Chromosome 6 ◽  
Whole Genome ◽  
Copy Number Alterations ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Background Over 90% of patients with Waldenström's Macroglobulinemia (WM), and 50-80% of patients with the precursor condition, IgM MGUS, express MYD88 L265P. These findings suggest that other mutations may support progression of IgM MGUS to WM. Chromosomal aberrations including large losses in 6q are commonly present in WM patients, though the gene loss accounting for WM pathogenesis remains unclear. We therefore sought to delineate copy number alterations (CNA) and structural variants using whole genome sequencing (WGS) in order to more clearly define other important gene alterations in WM. Methods DNA from CD19+ bone marrow lymphoplasmacytic lymphoma cells (LPC) and CD19-depleted peripheral blood mononuclear cells from 10 WM patients was used for paired tumor/germline analysis by WGS. Coverage in the tumor sample was divided by the coverage in the paired germline sample for each matching position, resulting in coverage ratios for each 100Kb window. Statistically significant windows within each genome were then analyzed across the cohort by randomizing the coverage positions to assess the probability of observing the given frequency of a CNA by random chance. TaqMan quantitative polymerase chain reaction (PCR) copy number assays was used to validate findings. Translocations were validated by Sanger sequencing across the breakpoint including flanking sequences. Results Functional annotation for identified CNAs was undertaken using Ingenuity Pathway Analysis that revealed a significant enrichment for pathways dysregulated in B-cell malignancies (Table 1). Iteratively randomizing the genomic position of CNAs not related to the chromosome 6 deletions revealed a greater than 3 fold increase in the targeting of COSMIC genes than expected by chance (p< 0.001). Affected genes in the COSMIC census were BTG1 (9/10; 90%), FOXP1 (7/10; 70%), FNBP1 (7/10; 70%), CD74 (7/10; 70%), TOP1 (6/10; 60%), MYB (5/10; 50%), CBLB (5/10; 50%), ETV6 (5/10; 50%), TNFAIP3 (5/10; 50%), FBXW7 (5/10; 50%), PRDM1 (5/10; 50%), TFE3 (4/10; 40%), JAK1 (4/10; 40%), MAML2 (4/10; 40%), FAM46C (4/10; 40%), EBF1 (4/10; 40%), STL (4/10; 40%), and BIRC3 (4/10; 40%). Other affected genes of interested included PRDM2 (8/10; 80%), HIVEP2 (8/10; 80%), ARID1B (7/10; 70%) as well as LYN (7/10; 70%). There were no singular regions of statistical significance in 6q to denote a minimally deleted region though neither of the previously suspected target genes for 6q loss, PRDM1 and TNFAIP3, were included in the regions of highest statistical significance. Losses in HIVEP2 (8/10; 80%) as well as ARID1B (7/10; 70%) and BCLAF1 (7/10; 70%) constituted the most common deletions in chromosome 6, and were present in patients with and without the large-scale losses in 6q. While no recurrent translocations were noted in this study, 2 or the 5 (40%) of the 6q deletions corresponded with translocation events. In one case, this was a result of chromothripsis focused on 6q while in the other case, a t(6;X) translocation linked to the amplification of Xq was identified. Validation studies confirmed presence of somatic deletions in BTG1 (4/5; 80%) at Chr. 12q21.33, HIVEP2 (4/5; 80%) at 6q24.2, LYN (3/5 60%) at 8q12.1, PLEKHG1 (3/5; 60%) at 6q25.1, ARID1B (3/5 60%) at 6q25.1, PDRM2 (2/5; 40%) at 1p36.21, FOXP1 (2/5; 40%) at 3p13, and MKLN1 (2/5 40%) at 7q32. As some CVAs were subclonal, we validated the correlation between the PCR relative copy number and WGS coverage predictions (rho = .926; p =2.2x10-16). Conclusions Highly recurrent CNAs are present in WM LPCs that include genes with critical regulatory roles in lymphocytic growth and survival signaling. Disclosures: No relevant conflicts of interest to declare.

Use of whole genome sequencing to identify highly recurrent somatic mutations in Waldenström’s macroglobulinemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8107-8107
Author(s):  
Zachary R Hunter ◽  
Lian Xu ◽  
Guang Yang ◽  
Yangsheng Zhou ◽  
Xia Liu ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Sanger Sequencing ◽  
Whole Genome ◽  
Waldenström’S Macroglobulinemia ◽  
Terminal Domain ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia ◽  
Myd88 L265p

8107 Background: Waldenstrom’s Macroglobulinemia (WM) is an IgM secreting lymphoplasmacytic lymphoma. The genetic basis for this disease remains to be clarified. Methods: We performed whole genome sequencing (WGS) using CD19+ selected bone marrow lymphoplasmacytic cells (LPC) from 30 WM patients. For 10 of these patients, paired CD19+ depleted peripheral blood samples were used for WGS as normal controls. Results: The most common somatic variants identified and validated by Sanger sequencing included MYD88 L265P, an activating mutation for IRAK/TRAF6/NFKB and MAPK signaling, which was observed in 27/30 (90%) patients; the N-terminal domain of CXCR4, which included mutations associated with WHIM syndrome and confer constitutive CXCR4 signaling resulting from dysfunctional receptor endocytosis, a finding observed in 8/30 (27%) patients, and ARID1A (5/30; 17%), a tumor suppressor gene. Less common somatic variants were also identified in MUC16 (4/30; 13%), TRAF2 (3/30; 10%), TRRAP (3/30; 10%) and MYBBP1A (2/30; 7%). Conclusions: Using WGS and confirmatory Sanger sequencing, we have identified several somatic variants with oncogenic function, the most common of which include MYD88 L265P, the N-terminal domain of CXCR4, and ARID1A.

Whole Genome Sequencing Reveals a Widely Expressed Mutation (MYD88 L265P) with Oncogenic Activity in Waldenstrom's Macroglobulinemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 300-300 ◽  
Author(s):  
Steven P Treon ◽  
Lian Xu ◽  
Yangsheng Zhou ◽  
Xia Liu ◽  
Guang Yang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Tumor Cells ◽  
Genome Sequencing ◽  
Sanger Sequencing ◽  
Whole Genome ◽  
Waldenström’S Macroglobulinemia ◽  
Oncogenic Activity ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenström's Macroglobulinemia ◽  
Myd88 L265p

Abstract Abstract 300 We performed whole genome sequencing (WGS) of lymphoplasmacytic cells from 30 Waldenstrom's Macroglobulinemia (WM) patients, with paired normal tissue sequencing for 10 patients. Tumor and normal genomes were both sequenced to an average of 66X coverage of mapped individual reads. A recurring sequence variant at position 38182641 in chromosome 3p22.2 was identified which resulted in a single nucleotide change from T®C in the myeloid differentiation primary response (MYD88) gene, and a predicted non-synonymous change at amino acid position 265 from leucine to proline (L265P). This variant was the most common of a median of 3,419 (range 2,540–4,011) somatic variants identified by WGS in paired patients, and was present in tumor cells from all 10 paired patients, and 16 of 20 unpaired patients. For 22 of 26 patients, the MYD88 L265P variant was heterozygous, whereas in 4 patients an acquired UPD event at 3p22.2 resulted in homozygous presence of the variant in at least a subset of tumor cells. Sanger sequencing confirmed the presence of the MYD88 L265P variant in all 26 patient tumor samples revealed by WGS, as well as in one additional patient's tumor sample that was not identified by the variant calling algorithms but for whom 12% of the WGS read level mappings showed the MYD88 L265P variant. In contrast, the MYD88 L265P variant was absent in normal paired tissues. Sanger sequencing therefore confirmed the somatic presence of the MYD88 L265P variant in tumor cells from 27 of 30 (90%) WM patients, and also identified this variant in BCWM.1 and MWCL-1 WM cells. In contrast, the MYD88 L265P variant was absent in CD138+ selected tumor cells from 8 of 8 multiple myeloma (MM) patients, and CD19+ cells from 12 of 12 healthy individuals, as well as in 7 of 8 patients with IgM monoclonal gammopathy of unknown significance (MGUS), in whom absence of the MYD88 L265P variant was further confirmed by TA cloning and sequencing of at least 100 clones. In the sole IgM MGUS patient in whom the MYD88 L265P mutation was detected, subsequent disease evolution occurred. Importantly, knock-down of MYD88 expression by lentiviral transduction led to loss of NF-κβ signaling and apoptosis of both BCWM.1 and MWCL-1 WM cells, with enhanced survival observed by complementary transduction with MYD88 L265P versus MYD88 wild type. The results of these studies therefore demonstrate a widely expressed somatic variant (MYD88 L265P) in malignant LPC of WM, whose presence confers oncogenic activity, and which may help distinguish WM disease from IgM MGUS or MM. Disclosures: No relevant conflicts of interest to declare.

Histone Deacetylase Inhibitors Demonstrate Significant Preclinical Activity as Single Agents, and in Combination with Bortezomib in Waldenstrom's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4785-4785
Author(s):  
Jenny Sun ◽  
Lian Xu ◽  
Hsiuyi Tseng ◽  
Bryan Ciccarelli ◽  
Mariateresa Fulciniti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Histone Deacetylase Inhibitors ◽  
Conflicts Of Interest ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Waldenström’S Macroglobulinemia ◽  
Over Expression ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 4785 Waldenstrom's Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration of CD19+ cells and production of a monoclonal IgM protein. Despite advances in treatment, WM remains incurable. As part of these efforts we sought to define the role of HDAC-inhibitors in WM. Gene expression profiling of bone marrow CD19+ cells from 30 WM patients and 10 healthy donors showed over-expression of HDAC4, HDAC9, and Sirt5 in WM patients. Evaluation of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA or Vorinostat), Trichostatin A (TSA), LBH-589 (Panobinostat), and sirtinol demonstrated dose dependent killing of BCWM.1 cells with IC50 of 3.5 uM, 70 nM, 0.8 uM, and 30 uM, respectively, whilst the combination of these agents with bortezomib resulted in at least additive tumor cell killing. TSA is more potent than bortezomib in inducing apoptosis in primary WM tumor cells in patients with prior treatment. TSA and bortezomib showed synergistic effect in 25% of the patients samples tested. We also observed that TSA and bortezomib-induced apoptosis of BCWM.1 cells depended on the activation of a similar set of caspases. Conversely, changes in cell cycle regulators were distinctly different between TSA and bortezomib treated BCWM.1 cells. The results of these studies demonstrate over-expression of distinct members of HDAC in WM cells, and provide a framework for the examination of HDAC-inhibitors as monotherapy, as well as combination therapy with bortezomib in the treatment of WM. Disclosures: No relevant conflicts of interest to declare.

Genome Wide Association Studies of Familial Waldenstrom's Macroglobulinemia (WM) Reveals a Loss of GSTM1 Is Common in Families with a History of B-Cell Disorders but Not in Those with a History Specific for WM.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 762-762
Author(s):  
Zachary Hunter ◽  
Christina Hanzis ◽  
Thea Ioakimidis ◽  
Christopher J Patterson ◽  
Bryan Ciccarelli ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Association Studies ◽  
Family Members ◽  
Genome Wide Association Studies ◽  
Waldenström’S Macroglobulinemia ◽  
Genome Wide ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 762 Background: The existence of a familial form of Waldenstrom's Macroglobulinemia (WM) has previously been described by us and others. Up to 20% of WM patients have a first degree relative with either WM, or a closely related B-cell disorder. The genetic basis for these findings has so far remained elusive. Patients and Methods: As part of these efforts, we enrolled 482 WM patients and their first and second degree family members, for a total of 148 families. Families were then classified as follows: Sporadic (Only 1 case of WM present); Familial WM Only (if ≥ 2 cases of WM were present); Familial Mixed B-cell (if only the proband had WM, and other B-cell disorders were present in other family members). Detailed medical as well as familial history for cancer and autoimmune disorders was collected, along with complete blood counts, quantitative immunoglobulins, and serum protein electrophoresis for all participants. Buccal and peripheral blood DNA samples were also collected. Genome wide association studies were run on peripheral blood DNA samples using SNP 6.0 platform from Affymetrix, and analyzed using R (R project for statistical computing) and the Affymetrix Genotyping Console. Data from 99 individuals was available for this analysis. Results: Among the 148 families enrolled, 89 (60.1%), 17 (11.5%), and 42 (28.4%) were classified as Sporadic, Familial WM Only, and Familial Mixed B-cell Cohorts. Analysis of the SNP 6.0 data revealed that copy number polymorphism (CNP) 88 was strongly associated with Familial Mixed B-cell presentation. A copy number of 0 for CNP88 was found in 2/5 (40%) probands (WM patients) from the Sporadic Cohort; 1/6 (16.7%) patients from the Familial WM Only Cohort; and 8/9 (88.9%) patients from the Familial Mixed B-cell Cohort (p= 0.011 and 0.09 vs. Sporadic and Familial WM Only Cohorts, respectively). Among proband family members, a copy number of 0 for CNP88 was found in 7/15 (46.7%) individuals from the Sporadic Cohort; 9/26 (34.6%) individuals from the Familial WM Only Cohort; and 34/37 (91.9%) individuals from the Familial Mixed B-cell Cohort (p<0.0001 versus Sporadic and Familial WM Only Cohorts). Very importantly, SNP 6.0 analysis revealed that the genomic region covered by CNP88 only affected the glutathione S-transferase gene GSTM1. Conclusions: The results of these studies implicate the homozygous deletion of GSTM1 in the Familial Mixed B-cell presentation for Waldenstrom's Macroglobulinemia. These findings are invariably germain not only to WM predisposition, but also to other closely related B-cell disorders which cluster with Familial WM. Disclosures: No relevant conflicts of interest to declare.

Associated Malignancies Among Patients and Kin with Waldenstrom's Macroglobulinemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4159-4159
Author(s):  
Christina Hanzis ◽  
Zachary Hunter ◽  
Robert Manning ◽  
Megan Lewicki ◽  
Philip Brodsky ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Family Members ◽  
Skin Melanoma ◽  
Waldenström’S Macroglobulinemia ◽  
Familial Predisposition ◽  
Increased Risk ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 4159 Waldenstrom's macroglobulinemia (WM) is a B-cell malignancy characterized as an IgM secreting lymphoplasmacytic lymphoma. Familial predisposition is common in WM. Studies to date by us and others have revealed three identifiable clinical subtypes for WM predisposition: * Sporadic; proband has WM, but there is an absence of WM or other B-cell disorders in other family members; * Familial, Mixed B-cell Disorders Subtype; proband has WM, and various B-cell disorders are manifested by other family members. * Familial, WM Only Subtype; proband has WM, and only WM is present in other family members; While these studies suggest a separate genetic predisposition for WM, the correlation of additional cancer risk among all patients with WM and their kin, and well as those sub typed by familial WM predisposition may herald important information for common genetic risks to cancer. We therefore examined the incidence of additional malignancies in 923 consecutive WM patients seen at our Institution, and characterized the frequencies of additional malignancies based on familial subtype and against SEER data. In addition, we also characterized the incidence of solid cancers in kin of WM patients, and sub typed these cancers based on familial WM presentation. Of the 923 patients, 221 (23.9%) patients had at least one additional malignancy to WM. Among these patients, 32 had 2, and 4 (0.43%) had 3 additional malignancies. For 167/221 (75.5%), the associated cancers were diagnosed before WM. The associated malignancies for all patients were as follows: Prostate (n=53; 9.2% of all males); Breast (n=27; 7.7% of all females); Skin (Basal and Squamous; n=61; 6.6%); Skin (Melanoma; n=16; 1.7%); Lung (n=12; 1.3%); Thyroid (n=10; 1.1%); Colorectal (n=7; 0.8%); Bladder (n=8; 0.9%) Other B-cell Malignancies (n=18; 2.0%); Renal (n=6; 0.7%); MDS (n=6; 0.65%); Other (n=11; 1.2%). The incidence of Lung (p=0.002) and Prostate (p=0.07) were higher among WM patients with Familial, Mixed B-cell Disorders Subtype. To avoid potential treatment related impact on additional cancer development, we next adjusted the observed versus expected frequencies based on SEER-17 data. The age adjusted incidence for development of any malignancy among WM patients was 7.6 fold higher when the development of another cancer antedated the diagnosis of WM. Among all WM patients, the incidence of solid cancers among first degree kin were as follows: Prostate (n=98; 10.6%); Breast (n=133; 14.4%); Skin (Basal and Squamous; n=21; 2.3%); Skin (Melanoma; n=21; 2.3%); Lung (n=116; 12.5%); Thyroid (n=9; 1.0%), Colorectal (n=79; 8.6%); Renal (n=8; 0.9%); and Gastric (n=20; 2.2%). The incidence of Breast (p=0.0098), and Skin (Melanoma) (p=0.037) cancers were higher among first degree kin of patients with the Sporadic versus Familial, Mixed B-cell Disorders Subtype. In summary, the above data suggest an increased risk for additional cancers among all WM patients, as well as specific risks for lung and prostate cancer among patients with Familial, Mixed B-cell Disorders Subtype. Moreover, these data also show the association of specific types of solid cancers in first degree kin of WM patients, particularly for WM patients with the Sporadic Subtype. n= Age (Yrs) Gender % Treated Additional Cancers Sporadic 666 60 (29–91) 64% M; 36% F 515 (77%) 163 (24.4%) Familial, Mixed B–cell Disorders 212 58 (36–85) 57% M; 43% F 156 (73%) 50 (23.5%) Familial, WM Only 45 61 (35–89) 56% M; 44% F 35 (77%) 8 (17.7%) Total 923 59 (29–91) 62% M; 38% F 706 (76.4%) 221 (23.9%) Disclosures: No relevant conflicts of interest to declare.

Comprehensive Assessment of Cytokines and Chemokines In Patients with Waldenstrom's Macroglobulinemia Reveals a Distinct Profile with Pathobiological and Clinical Relevance

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1911-1911
Author(s):  
Megan Lewicki ◽  
Bryan Ciccarelli ◽  
Zachary Hunter ◽  
Philip Brodsky ◽  
Robert Manning ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Regulation ◽  
Waldenström’S Macroglobulinemia ◽  
Gm Csf ◽  
Cytokines And Chemokines ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 1911 Waldenstrom's macroglobulinemia (WM) is a B-cell lymphoplasmacytic disorder characterized by elevated clonal IgM secretion and bone marrow infiltration. Dysregulation of plasma cytokines and chemokines have been described in related malignancies, though large scale comparative efforts to WM have been limited. We therefore evaluated the levels of 20 cytokines, 27 chemokines, and soluble CD27 (sCD27) given the putative memory B-cell origin of WM in peripheral blood derived plasma obtained from 54 patients with WM, 31 patients with Multiple Myeloma (MM), and 37 patients with monoclonal gammopathy of unknown significance (MGUS) using the Bio-Plex Pro Human Cytokine 27-plex Assay and the Bender instant soluble CD27 ELISA. Twenty-six age-matched normal donors (ND) were used as controls. Among WM patients, we detected significantly higher levels of the cytokines IL-1Rα (p<0.001), IL-5 (p=0.009), IL-6 (p=0.017), IL-8 (p<0.001), IL-10 (p<0.001), IL-17 (p<0.001), INFg (p=0.022) and GM-CSF (p<0.001), as well as the chemokines CCL2 (p<0.001), CCL3 (p<0.001), and CXCL8 (p<0.001). IL-2 (p<0.001), IL-9 (p< 0.001), IL-15 (p < 0.001), FGF2 (p<0.001), and sCD27 (p<0.001) levels were also significantly increased, while IL-7 levels were decreased (p<0.001). The same pattern of up and down-regulation was also detected in MM and MGUS, suggesting these diseases share some pathophysiological characteristics. In distinction, we observed decreased levels of CCL11 (p<0.02) and RANTES <0.02) only among WM patients in comparison to MM, MGUS, and NDs. Taken together, these data highlight similarities and differences in cytokine and chemokine profile for WM patients, which may be relevant to WM pathogenesis (Figure 1). In addition, sCD27 was associated with several clinical markers, notably correlating negatively with B2M (rho = -0.42, p = 0.016) and positively with CD8+ T-cell percentage (rho = 0.44, p < 0.001). sCD27 was also increased 1.9 fold in WM patients with a familial history of psoriasis (p = 0.021, n = 6). Among the cytokines and chemokines, GM-CSF was decreased 1.7 fold in the presence of lymphadenopathy (p = 0.003, n = 15), and IL-7 and CXCL10 were both increased in the four previously treated patients (fold = 5.5, p = 0.005; fold = 3.4, p = 0.003). In conclusion, there is significant cytokine, chemokine, and soluble CD27 dysregulation in WM, MM, and MGUS corresponding to important clinical correlations in WM. In addition to B-cell regulation, several of these dysregulations are also involved in T-cell regulation, signifying a need for further understanding of T-cell involvement in WM. These data demonstrate that further investigation of cytokine involvement in the pathogenesis and prognosis of these diseases is warranted. Disclosures: No relevant conflicts of interest to declare.

Bing-Neel Syndrome: A Rare Complication of Waldenstrom’s Macroglobulinemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5480-5480
Author(s):  
Sergio A. Sanchez-Guerrero ◽  
Steven P. Treon ◽  
Luis Guevara-Arnal ◽  
Akram Darwich ◽  
Andrea Cardenas-Ortega ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Conflicts Of Interest ◽  
Rare Complication ◽  
Waldenström’S Macroglobulinemia ◽  
Neoplastic Cells ◽  
Blurred Vision ◽  
Neck Stiffness ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract A sixty-one year-old Hispanic female with Waldenstrom’s Macroglobulinemia diagnosed in 2011 and successfully treated with 6 monthly cycles of Cyclophosphamide, Rituximab and Dexamethasone (CDR) from 12/11 through 5/12 was then put on a two-year maintenance scheme with Rituximab every three months. In February, 2014 (six months before the end of the planned treatment), she came to the ER complaining with severe headache, aphasia and blurred vision. A stroke was initially ruled out and she received Paracetamol with partial improvement. Nonetheless, symptoms re-appeared accompanied with disorientation and agitation. Antipsychotic medication was given with no improvement. On PE she was disoriented with aphasia, paraparetic and neck stiffness suggestive of meningitis. Blood tests, a MRI and lumbar puncture were performed showing leptomeningeal hyperintensity with no signs of encephalitis (Figure 1). Figure 1 Leptomeningeal reinforcement as seen in MRI. Figure 1. Leptomeningeal reinforcement as seen in MRI. CSF analysis showed WBC 64 cells/µL, (95% MNC), glucose= 9.8 mg/dL and proteins= 110 g/dL. Gram dye was negative. A geneXpert for Tuberculosis was negative. CSF cytology showed an infiltration of lymphoid neoplastic cells confirmed by cytochemistry (Figures 2a and 2b). Figure 2a: CD 20+ and 2b: kappa + neoplastic cells in CSF Figure 2a:. CD 20+ and 2b: kappa + neoplastic cells in CSF Figure 3 Figure 3. With these results a Bing Neel syndrome was diagnosed and IT Methotrexate was given for a total of 6 doses resulting in a nice reduction of the neoplastic cells. However, she relapsed in April/2014 and IV Fludarabine was started. We are planning to add IT liposomal Cytarabine. Additionally, MYD 88 gene mutation was detected. DISCUSSION: There are only 33 reported cases of Bing-Neel syndrome in the medical literature for the last 80 years and this one has been confirmed with the newest tools such as: MRI, cytochemistry and gene mutation. CONCLUSION: Bing-Neel syndrome should be suspected in every patient with Waldenstrom’s Macroglobulinemia and CNS impairment. Disclosures No relevant conflicts of interest to declare.

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