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  • American Society of Hematology  (14)
  • Patterson, Christopher J  (14)
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  • American Society of Hematology  (14)
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  • 1
    Online Resource
    Online Resource
    Aberrant DNA Methylation and Transcriptional Silencing of DLC-1 in Waldenstrom's Macroglobulinemia.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2954-2954
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2954-2954
    Abstract: Abstract 2954 Poster Board II-930 The deleted in liver cancer-1 (DLC-1) gene encodes a Rho GTPase activating protein (RhoGAP) with potential tumor-suppressor activity. Hypermethylation in the DLC-1 promoter is an aberrant epigenetic modification associated with transcriptional silencing of DLC-1 in various types of human cancers. To explore the epigenetic alteration of DLC-1 in Waldenström's macroglobulinemia (WM), we investigated the methylation status of the DLC-1 promoter and its correlation with DLC-1 mRNA expression in cell lines and primary WM patient samples. Initial analysis using methylation-specific PCR (MSP) showed that DLC-1 promoter was completely methylated in WM-WSU and partially methylated in BCWM.1. Using quantitative RT-PCR, DLC-1 mRNA expression was detectable in BCWM.1, but not WM-WSU. These results suggested a correlation between the DLC-1 methylation status and mRNA expression. Similarly, among multiple myeloma (MM) cell lines, we showed that RPMI and U266 exhibited complete methylation, whereas INA6 showed partial methylation, and no methylation was detectable in MM1S and MM1R cells. Similar in WM cells, DLC-1 methylation status was highly correlated with the mRNA expression in these MM cell lines. Of 37 WM patient samples examined, 24 (65%) exhibited methylation in the DLC-1 promoter. In contrast, no methylation of DLC-1 was observed in 4 healthy volunteers. The methylation status was further confirmed using bisulfite DNA sequencing in a subset of WM patients. Quantitative RT-PCR analysis showed that DLC-1 mRNA expression was significantly lower in WM patients compared to healthy volunteers (p=0.001). Treatment with demethylation agents azacytidine or 5-aza-deoxycytidine resulted in significant reactivation of DLC-1 transcription in the WM cell lines WM-WSU and BCWM.1. In addition, a synergistic induction of DLC-1 transcription was observed in the presence of azacytidine and the HDAC inhibitor Vorinostat in BCWM.1 and primary WM patient cells. Moreover, functional studies showed that overexpression of DLC-1 induced cell growth arrest and apoptosis in BCWM.1. DLC-1 methylation status was also correlated with serum sCD27 levels in WM patients (p=0.004), which is secreted by WM cells, serves as a marker of disease burden and facilitates CD40L directed paracrine stimulation by mast cells. Taken together, these results suggest that the down-regulation of DLC-1 via aberrant DNA methylation plays a role in the pathogenesis of WM, and represents a novel therapeutic target in the treatment of WM. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2954.2954
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    Online Resource
    Online Resource
    Polymorphisms of FcγRIIA, FcγRIIB, and FcγRIIIA and Therapeutic Response to Rituximab Combination Therapy in Patients with Waldenstrom's Macroglobulinemia.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2949-2949
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2949-2949
    Abstract: Abstract 2949 Poster Board II-925 Background: The efficacy of rituximab is dependent on a number of host immune interactions, including binding through excitatory (FcγRIIA, FcγRIIIA) as well as inhibitory (FcγRIIB) Fcγ receptors. In previous studies, we showed that polymorphisms in FcγRIIIA-158 predicted outcome to single agent rituximab therapy. Patients displaying L/H or L/R at FcγRIIIA-48 or at least one valine (V/V or V/F) at FcγRIIIA-158 demonstrated greater responses to rituximab versus those patients who expressed FcγRIIIA-48-L/L or FcγRIIIA-158 F/F, respectively (JCO 23:474). The predictive role of FcγRIIIA polymorphisms in patients receiving combination therapy with rituximab has not been addressed to date in WM. We therefore investigated the predictive role of FcγRIIIA-48, -158, as well as other important polymorphisms implicated in modulating IgG antibody binding and activation: FcγRIIA-27, -131, and FcγRIIB-187 in 65 patients with WM who received combination rituximab therapy. Patients and Methods: Sixty-four WM patients with a median age of 61, prior therapies of 0, IgM of 3,540 mg/dL, Hct of 32.3%, B2M of 2.7 g/L, who participated on a clinical study and whose outcomes have previously been reported were included in this analysis. Treatment included rituximab in combination with cyclophosphamide (n=43), thalidomide (n=14), or lenalidomide (n=7). Categorical responses for all patients were as follows: CR/VGPR 7 (11%); PR (n=30; 46.2%); MR (n=18; 27.7%); Non-Responders (n=9; 14.1%) for an overall response rate of 86%. Twenty seven patients have progressed with a median follow-up of 19.4 months. Polymorphic variants at FcγRIIA-27, -131, FcγRIIB-187, and FcγRIIIA-48, -158 were determined by Taq Man real time PCR analysis and sequencing, and impact on overall response, categorical response rates, and progression free survival determined. Results: The expression of H/H at FcγRIIA-131, or at least one valine (V/V or V/F) at FcγRIIIA-158 was associated with improved categorical response, particularly the attainment of CR/VGPR. For FcγRIIA-131, H/H was expressed in 2/9 (22.22%) WM patients who were non-responders; 13/38 (34.2%) patients attaining a major (≥ PR) response, and 4/7 (57.14%) patients who attained a CR/VGPR. For FcγRIIIA-158, the expression of at least one valine was observed in 3/9 (33.3%) WM patients who were non-responders; 20/38 (52.62%) patients attaining a major (≥ PR) response, and 5/7 (71.42%) patients who attained a CR/VGPR. Polymorphisms at FcγRIIA-27, and FcγRIIB-187 showed no association with response. The expression of L/H or L/R at FcγRIIIA-48 was observed in 3/7 (42.86%) patients with CR/VGPR, whereas 2/9 (22.22%) of patients who were non-responders expressed this polymorphism. Subset analysis showed that among patients who received cyclophosphamide based therapy, no differences in polymorphic variation for FcγRIIA-131, FcγRIIIA-48, and -158 were observed between non-responders, major responders and those achieving CR/VGPR. Conclusions: Taken together, the results of this study support a role for the use of FcγRIIA-131, FcγRIII-158, and possibly FcγRIIA-48 as determinants of better categorical responses in WM patients receiving combination therapy with an immunomodulatory agent. The combined use of cyclophosphamide with rituximab therapy appears to negate the inferior outcomes predicted by polymorphic variants in FcγRIIA-131, FcγRIIIA-48, and -158 which have previously been shown to be associated with lower response rates to single agent rituximab therapy. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2949.2949
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    Next Generation Sequencing Identifies a Distinct Transcriptional Profile, Including Isoform Dysregulation That Segue with Genomic Alterations in Waldenstrom's Macoglobulinemia
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 128-128
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 128-128
    Abstract: Background: Whole genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4 and ARID1A, as well as gene losses in Waldenström's Macroglobulinemia (WM) (NEJM 367(9):826-33; Blood 123(11):1637-46). At least three genomic defined subpopulations of WM have been identified based on MYD88 and CXCR4 mutation status (Blood 123(18):2791-6).The regulatory impact for these genomic alterations remain to be clarified. Methods: Next generation transcriptome profiling was performed using Illumina HiSeq. RNA was isolated from CD19-selected bone marrow cells from 57 WM patients, as well as memory (CD19+CD27+) and non-memory (CD19+CD27-) B-cells from 9 healthy donors. Differential gene expression analysis was performed based on MYD88, CXCR4 and ARID1A mutation status, as well as common cytogenetic abnormalities encountered in WM including amplifications in chromosomes 3q, 4, 6p, and deletions in 6q. Reads were aligned to KnownGene HG19/GRCh37 reference using STAR. Read counts per gene were obtained using featureCounts from Rsubread, and analyzed using voom from the edgeR/limma Bioconductor packages in R. Differential isoform expression was assessed using the Cufflinks software suite. Functional enrichment analysis was conducted using Ingenuity Pathway Analysis. Results: Transcriptional profilingof WM cells showed a stronger correlation with healthy donor memory B-cells, their putative cell of origin. Differential gene expression analysis between WM patients and healthy donors generated a distinct transcriptional profile for WM that included dysregulation of PIM1, RGS7, IL11RA and EPHB4, as well as differential isoform usage in TP53, PRDM1 and XBP1. MYD88mutatedCXCR4wild-type(WT) WM patients consistently over-expressed genes unique to this cohort including, IL17RB, GPER, WNT5A, WNK2, CABELS1, and PRDM5. MYD88mutated patients who harbored nonsense (NS) or frame-shift (FS) mutations in CXCR4 showed functional enrichment of genes that indicated inhibition of Toll-like receptor inflammatory pathways. CXCR4 mutated patients showed strong up-regulation of CXCR7 and TSPAN33, and exhibited isoform level dysregulation of MEF2B, FOXO3, KDM2A and PRKAG2. Unsupervised clustering differentiated MYD88mutatedCXCR4WT from MYD88mutatedCXCR4NS/FS patients, while samples from MYD88WTCXCR4WT clustered with CXCR4NS/FS group. Clusters based on clonality and disease burden were also observed (Figure 1). CXCR4NS/FS transcripts were preferentially expressed over CXCR4WT transcripts despite the subclonal presence of CXCR4mutations. These findings were further validated by comparative DNA versus cDNA Sanger sequencing indicating allelic dysregulation within CXCR4NS/FS subclones. Controlling for MYD88 and CXCR4 mutation status, the presence of ARID1A mutations and cytogenetic abnormalities generated distinct transcriptional profiles. Random forest regression analysis identified subsets of genes strongly associated with bone marrow disease involvement, serum IgM and hemoglobin levels. Notably, increased bone marrow disease burden was associated with increased CXCL13, and decreased TP53 and RBL1 expression. Likewise, higher levels of serum IgM corresponded with increased IL27RA expression. Conclusion: Using next generation sequencing, we have identified a distinct transcriptional profile, including isoform dysregulation that segue with highly prevalent genomic mutations in WM. The findings provide valuable insights into the molecular pathogenesis and clinical presentation of WM. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.128.128
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    Whole Genome Sequencing Reveals a Widely Expressed Mutation (MYD88 L265P) with Oncogenic Activity in Waldenstrom's Macroglobulinemia
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 300-300
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 300-300
    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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.300.300
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    Online Resource
    Online Resource
    Patients with Waldenstrom's Macroglobulinemia Are Often Hypoferremic That Is Refractory to Oral Iron Repletion and Responsive to Parental Iron Infusions, and Demonstrate Elevated Levels of Hepcidin.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2952-2952
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2952-2952
    Abstract: Abstract 2952 Poster Board II-928 Background: Patients with Waldenstrom's macroglobulinemia (WM) often present with anemia, that can occur independent of bone marrow disease involvement, serum IgM levels, and in the absence of any hemolysis (Treon, Blood 2009). Iron deficiency is commonly observed in WM patients, and is often oral iron refractory. Parenteral administration of iron (Ferrlicit) in such patients can lead to improvements in hematocrit in patients who are oral iron refractory as shown below in Table 1: As such, we investigated mechanisms by which oral iron uptake could be impaired in patients with WM. Hepcidin is a peptide which acts as a master regulator of iron homeostasis by binding to and disabling the only known iron-export protein, ferroportin, resulting in the inhibition of iron transfer from enterocytes and macrophages into the circulation. We therefore sought to delineate the role of Hepcidin in WM patients presenting with and without anemia, and in those patients who did not respond to oral iron intake. Patients and Methods: Serum levels of Hepcidin were determined in 53 previously untreated patients with WM [Median Age: 63; BM Involvement 40%; Beta 2 Microglobulin (B2M) 2.6 g/L; Hematocrit 34.2%; Iron 67 ug/dL; TIBC 321 ug/dL] along with 20 healthy donors [Median Age: 63.5, Female N=8, Male N=12] using the Hepcidin-P competitive ELISA for hepcidin-25, the biologically-active form of the hormone [Intrinsic LifeSciences, La Jolla, CA USA]. Of the patients examined, 45 were anemic, 12 were hypoferremic [ 〈 37-170 mg/dL]. All but 5 individuals had normal TIBC levels [210-480 mg/dL] . Results: Serum Hepcidin levels were elevated among all WM patients [107.5 ng/mL, range 11.3-689 ng/mL] versus healthy donors [91.8 ng/mL, range 12.2-211.6 ng/mL; p=.04] . Levels of Hepcidin positively correlated with BM disease involvement (p=0.004; Spearmans rho=0.4), and inversely with hematocrit (p=0.08; Spearman's rho=-.24) [Figure 1,2]. Among the 45 WM patients who demonstrated anemia, the median level of Hepcidin was higher at 118.5 ng/mL [Range 11.3-689 ng/mL; p=0.025 versus healthy donors]. Among 5 WM patients who failed to respond to oral iron repletion and who subsequently responded to parenteral iron (Table 1), the median Hepcidin level was 189.1 (range 40.6-444.1 ng/mL). Among non-anemic WM patients, hepcidin levels were lower [66.5 ng/mL; range 31.7-401.8 ng/mL; p=0.35 versus anemic WM patients), though these patients demonstrated a lower bone marrow disease burden (30% vs. 50%; p=0.03). Conclusions: Hepcidin levels are elevated in patients with WM, and show a positive correlation with bone marrow disease burden, and an inverse relationship with hematocrit. Importantly, higher levels of Hepcidin may be associated with refractoriness to oral iron intake. Further studies addressing the role of Hepcidin in the management of WM related anemia are warranted. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2952.2952
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    Online Resource
    Online Resource
    Whole-Genome Sequencing Results From 30 Patients with Waldenstrom's Macroglobulinemia
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 434-434
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 434-434
    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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.434.434
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
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    Online Resource
    IgA and IgG Hypogammaglobulinemia Does Not Predict for Recurrent Infection Risk and Persists Despite Therapeutic Response in Patients with Waldentrom's Macroglobulinemia.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1947-1947
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1947-1947
    Abstract: Abstract 1947 Poster Board I-970 Recurrent infections are commonly observed among patients with WM, and may be related to the presence of IgA and IgG hypogammaglobulinemia. The etiology for this finding remains unclear, and has been speculated to be on the basis of tumor-induced suppression. We therefore evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 untreated WM patients and addressed the associated clinicopathological findings, and impact of therapy. The median age of these patients was 60, median IgM was 2,910, and median bone marrow (BM) infiltration was 40%. Of these patients, 131 (63.3%) and 120 (58.0%) patients demonstrated decreased serum IgA and IgG levels respectively, while 102 (49.3%) of these patients were abnormally low for both. BM infiltration, serum IgM levels, complete blood counts, absolute lymphocyte counts, b2-microglobulin, or the WM International Prognostic Scoring System score had no impact on the odds ratio of having IgA or IgG, or both IgA or IgG hypogammaglobulinemia by logistic regression analysis. The presence of adenopathy and/or splenomegaly was surprisingly associated with a lower incidence of hypogammaglobulinemia (p≤0.03). The presence of IgA, IgG or both IgA and IgG hypogammaglobulinemia did not predict for the occurrence of recurring infections, which were nearly all respiratory in nature and consisted of sinus (n=53; 25.85%), bronchial (n=16; 7.80%), unspecified upper respiratory tract (n=14; 6.83%), and pneumonic (n=7; 3.41%) infections. Lower IgA and IgG levels were however associated with disease progression in watch and wait patients. To understand the impact of WM directed therapeutic intervention on uninvolved immunoglobulin levels, we analyzed changes in IgA and IgG levels in a cohort of 93 patients who underwent treatment for WM. With a median follow-up of 12 months, no significant recovery in the median IgA and IgG levels was observed with any therapy during the course of follow-up, including in those patients who had follow-up in excess of 1 (n=46), 2 (n=25), and 3 (n=8) or more years post-therapy, and in those achieving a major remission including complete response. Lastly, we sequenced 8 genes (AICDA; BTK; CD40; CD154; NEMO, TACI, SH2D1A, UNG) implicated in immunoglobulin deficiency in 19 WM patients with IgA and/or IgG hypogammaglobulinemia. We observed an intronic variation at position c.1056-6T 〉 C in 2 patients, and a hemizygous missense mutation at c.337G 〉 A in another patient for NEMO, as well as a heterozygous missense mutation at c.425A 〉 T in the highly conserved catalytic site of UNG for one patient. The results of these studies demonstrate that IgA and IgG hypogammaglobulinemia is common, and does not predict for recurrent infection risk in WM. Moreover, IgA and IgG hypogammaglobulinemia persists despite therapeutic intervention and response. These studies highlight the importance for further investigations into the IgA and IgG hypogammaglobulinemia of WM, as well as the signaling pathways involved in B-cell differentiation and immunoglobulin heavy chain class switching in the pathogenesis of WM. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1947.1947
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Micro-RNA Expression Profiling Reveals Distinct Correlates to Disease Pathogenesis, and Identifies Novel Pathways Involved in Tumor Cell Senescence and IL-12A Signaling.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2950-2950
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2950-2950
    Abstract: Abstract 2950 Poster Board II-926 Background: Multiple studies in closely related diseases such as Chronic Lymphocytic Leukemia (CLL) have revealed distinct miRNA profiles. This increasing appreciation for the role of miRNA expression in disease pathogenesis and homeostasis within cancer biology lead us to profile the miRNA expression of CD19+ bone marrow cells from 11 patients with Waldenstrom's Macroglobulinemia (MR) and 5 healthy donors. The median age for patients was 72 years (range 49-81), WM ISS Prognostic Score was 1 (range 0-4), bone marrow disease involvement was 40% (range 5-80%), and serum IgM was 3,330 (range 202-6,110 mg/dL). Five patients (45.5%) were previously treated and 4 (36.4%) had extramedullary disease. Patients and Methods: CD19+ cells were selected using auto-MACs cell sorting (Miltayni Biotec) and total RNA was extracted with Trizol (Invitrogen). Micro-RNA profiling was conducted using TaqMan low density arrays (Applied Biosystems) allowing for stem-loop based qPCR detection of 670 miRNAs per sample. Results were validated using RT2 miRNA SYBR green based qPCR (SABiosciences). Relative quantification was calculated by ddCT using U6 endogenous controls and normalized to the first healthy donor sample. Results were analyzed using custom perl scripts running bootstrap calculated 95% CIs and approximate permutation testing from 10,000 resampling groups for both means and medians resulting in a robust and distribution independent characterization of each population. Additional Mann-Whitney-Wilcoxon, general linear modeling (GLM), ANOVA, and Spearman correlation testing was conducted using R (R Project for Statistical Computing). Results: We identified miR-29c (+3.2 fold), miR-339-5p (+2.0 fold), and miR-21 (+3.2 fold) as significantly up-regulated in WM patients (p 〈 0.006 for all). Down-regulated miRNAs included miR-324-3p (-2.0 fold), miR 875-5p (-3.2 fold) and miR-638 (-7.2 fold) (p 〈 0.006 for all). Analysis of these findings with clinical features revealed a positive correlation of miR-29c with serum IgM (rho=.65, p=0.03), using multivariate analysis that included age and previous treatment status (p 〈 0.001). Both miR-875-5p and miR324-3p inversely correlated with bone marrow disease involvement (rho 〈 -0.79, p 〈 0.005 for both), and both of these were found to be predictive under multivariate analysis (p 〈 0.001 and 〈 0.01 respectively). Furthermore, mir-638 was found to correlate with the presence of extramedullary disease (p=0.026). As some miRNAs are known to destroy their target mRNAs, we compared our findings to our existing gene expression profiling data using the Sanger miRBase Target Database. miR-29c was predicted to target MAD2L1BP (AKA p31comet, CTM2), a tumor senescence inducing protein whose expression is down-regulated in WM by gene expression profiling (-2.1 fold, p 〈 0.0001); in addition, miR-21 which is predicted to target IL-12A was also decreased by -2.0 fold by gene expression profiling (p=0.005). Conclusions: The above findings demonstrate a distinct miRNA profile in WM, and implicate several miRNAs in the pathogenesis of WM, including genes involved in the regulation of tumor cell senescence and IL-12A. These findings provide a framework for the exploration of novel signaling pathways and therapeutic approaches in WM. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2950.2950
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 9
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    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.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 762-762
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 762-762
    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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.762.762
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 10
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    A Somatic Variant in MYD88 (L265P) Revealed by Whole Genome Sequencing Differentiates Lymphoplasmacytic Lymphoma From Marginal Zone Lymphomas
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 261-261
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 261-261
    Abstract: Abstract 261 Lymphoplasmacytic (LPL) and marginal zone lymphoma (MZL) are distinct clinicopathological entities under the WHO classification system for B-cell lymphomas. Differentiation of LPL from MZL has been difficult due to overlapping clinical, morphological, histopathological, immunophenotypic, and cytogenetic features. We therefore sought to identify a molecular marker by which LPL could be differentiated from MZL. Using paired normal/tumor tissues from 10 LPL patients, whole genome sequencing was utilized to identify somatic variants. These studies identified a somatic variant at position 38182641 in chromosome 3p22.2 with 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) in 10 of 10 LPL patients. MYD88 L265P is an oncogenically active mutation in DLBCL ABC cell lines via activation of IRAK1/4/TRAF-6/NF-κβ signaling, and is present in tumors from 29% of patients with ABC subtype of DLBCL, and 6% of patients with MALT lymphomas (Ngo et al, Nature 2011, 470:115–119). Further to these efforts, we performed Sanger sequencing of MYD88 in malignant cells obtained from 51 patients with LPL, 49 of whom had an IgM monoclonal protein and were therefore classified as Waldenstrom's Macroglobulinemia (WM), and 2 with an IgG monoclonal protein, along with 46 patients with MZL, which included 21 Splenic (SMZL), 20 Extranodal (EMZL), and 5 Nodal (NMZL) Subtypes, as well as B-cells from 15 healthy donors. Among LPL patients, the MYD88 L265P variant was found in malignant cells from 46/51 (90.1%) cases, which included 44 patients with WM, and 2 patients with IgG LPL. Expression of the MYD88 L265P variant was heterozygous in 42, and homozygous in 4 LPL patients. By comparison, only 3/46 (6.5%) patients with MZL (1 SMZL; 1 EMZL; 1 NMZL) exhibited the MYD88 L265P variant which was heterozygous (p 〈 0.0001), and included 2 patients (1 SMZL, 1 NMZL) with extensive bone marrow involvement, a monoclonal IgM protein, and whose clinicopathological characteristics overlapped with LPL. By comparison, the MYD88 L265P variant was absent in CD19+ cells from all 15 healthy donors. The results of this study demonstrate that the MYD88 L265P mutation is widely expressed in patients with LPL, and can be used to differentiate LPL from MZL. Disclosures: Treon: Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.261.261
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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