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  • American Society of Hematology  (40)
  • 1
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    Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice
    American Society of Hematology ; 2007
    In:  Blood Vol. 109, No. 12 ( 2007-06-15), p. 5079-5086
    Details
    In: Blood, American Society of Hematology, Vol. 109, No. 12 ( 2007-06-15), p. 5079-5086
    Abstract: New Zealand black (NZB) mice with autoimmune and B lymphoproliferative disease (B-LPD) are a model for human chronic lymphocytic leukemia (CLL). A genomewide linkage scan of the NZB loci associated with lymphoma was conducted in F1 backcrosses of NZB and a control strain, DBA/2. Of 202 mice phenotyped for the presence or absence of LPD, surface maker expression, DNA content, and microsatellite polymorphisms, 74 had disease. The CD5+, IgM+, B220dim, hyperdiploid LPD was linked to 3 loci on chromosomes 14, 18, and 19 that are distinct from previously identified autoimmunity-associated loci. The region of synteny with mouse D14mit160 is the human 13q14 region, associated with human CLL, containing microRNAs mir-15a16-1. DNA sequencing of multiple NZB tissues identified a point mutation in the 3′ flanking sequence of the identical microRNA, mir-16-1, and this mutation was not present in other strains, including the nearest neighbor, NZW. Levels of miR-16 were decreased in NZB lymphoid tissue. Exogenous miR-16 delivered to an NZB malignant B-1 cell line resulted in cell-cycle alterations and increased apoptosis. Linkage of the mir-15a/16-1 complex and the development of B-LPD in this spontaneous mouse model suggest that the altered expression of the mir-15a/16-1 is the molecular lesion in CLL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2007-02-071225
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
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  • 2
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    Natural history of monoclonal B-cell lymphocytosis among relatives in CLL families
    American Society of Hematology ; 2021
    In:  Blood Vol. 137, No. 15 ( 2021-04-15), p. 2046-2056
    Details
    In: Blood, American Society of Hematology, Vol. 137, No. 15 ( 2021-04-15), p. 2046-2056
    Abstract: Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2020006322
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Differential Gene Expression in CLL Cells from Bone Marrow and Peripheral Blood Suggests a Role of Bone Marrow Stroma in Leukemic Cell Proliferation.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 708-708
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 708-708
    Abstract: Chronic lymphocytic leukemia (CLL) has been described as an accumulative disease of mature lymphocytes. In the peripheral blood (PB) CLL cells are in Go/G1-phase, and gene expression is most consistent with resting B-cells. However, a recent study demonstrated that a surprisingly large fraction of CLL cells are constantly turned over and that proliferation contributes significantly to the expansion of the clone. The sites where proliferation occurs are not well defined but likely include the bone marrow (BM) and/or lymphoid organs. Likewise, the signals governing proliferation of the leukemic cells are ill defined but there appears to be a role for CLL extrinsic factors including stroma cell interactions or antigen stimulation. We hypothesized that gene expression in BM-CLL cells differs from that in PB-CLL cells. Here we report our analysis of 8 pairs of matched CLL samples derived from 7 individuals in whom we simultaneously obtained PB and BM. All patients were untreated, 3 female, 4 male; in 2 the CLL cells expressed unmutated IgVH genes, and 4 were ZAP70 positive. After informed consent, we obtained a dedicated research aspirate. CD19 selection resulted in & gt;98% purity in all samples. PB-CLL cells express high levels of CXCR4, the receptor for SDF-1. As SDF-1 is expressed by BM stroma cells and CLL cells internalize CXCR4 after binding SDF-1 we measured CXCR4 expression by flow cytometry as an indicator of recent contact between leukemic cells and stroma. In PB, a mean of 63% (range 29–90%) of CLL cells expressed CXCR4 above isotype as compared to 30% (3–62%) of cells from the BM (p=0.007). Conversely, we followed CD69 expression as a marker of activation. In 5 of the 8 pairs CD69 was more highly expressed in BM than in PB derived CD19+ cells (p=0.005) indicating activation of the leukemic cells in the BM microenvironment. We performed gene expression analysis of total mRNA of all matched pairs on Affymetrix U133A 2.0 arrays according to standard protocols. We considered all genes with present calls in either PB-CLL or BM-CLL. The samples were normalized to correct for the individual to individual variance by first normalizing each individual’s PB and BM expression values by their PB value, and then averaging over the 8 individuals using GeneSpring software (Agilent). There were 543 genes with at least 1.5x higher expression in BM vs PB and 192 genes with at least 1.5x higher expression in PB versus BM at p & lt;0.05. Genes more highly expressed in the BM derived CD19-selected cells included topoisomerase II alpha, several cyclins, including cyclin D1, signal transduction components such as PI-3 kinase and components of the Wnt pathway, transcription factors and enhancers such as c-Fos and Sox-4 and several chemokines and chemokine receptors. Of note, there was no difference in the expression of ZAP70, LPL, ADAM29, Bcl-2 and Mcl-1 between the two sites. Our findings are consistent with a model in which CLL cells migrate along an SDF-1 chemokine gradient to the BM where they are stimulated in contact with BM-stroma cells. The higher expression of cell cycle genes in the BM resident CLL cells supports recent findings of a sizeable proliferating fraction of CLL cells and suggests that at least part of this proliferating pool resides in the BM. Ongoing analysis is directed at identifying signaling pathways contributing such proliferation signals.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.708.708
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
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  • 4
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    The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia
    American Society of Hematology ; 2011
    In:  Blood Vol. 117, No. 2 ( 2011-01-13), p. 563-574
    Details
    In: Blood, American Society of Hematology, Vol. 117, No. 2 ( 2011-01-13), p. 563-574
    Abstract: Chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes, involves blood, bone marrow, and secondary lymphoid organs such as the lymph nodes (LN). A role of the tissue microenvironment in the pathogenesis of CLL is hypothesized based on in vitro observations, but its contribution in vivo remains ill-defined. To elucidate the effects of tumor-host interactions in vivo, we purified tumor cells from 24 treatment-naive patients. Samples were obtained concurrently from blood, bone marrow, and/or LN and analyzed by gene expression profiling. We identified the LN as a key site in CLL pathogenesis. CLL cells in the LN showed up-regulation of gene signatures, indicating B-cell receptor (BCR) and nuclear factor-κB activation. Consistent with antigen-dependent BCR signaling and canonical nuclear factor-κB activation, we detected phosphorylation of SYK and IκBα, respectively. Expression of BCR target genes was stronger in clinically more aggressive CLL, indicating more effective BCR signaling in this subtype in vivo. Tumor proliferation, quantified by the expression of the E2F and c-MYC target genes and verified with Ki67 staining by flow cytometry, was highest in the LN and was correlated with clinical disease progression. These data identify the disruption of tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic strategies in CLL. This study is registered at http://clinicaltrials.gov as NCT00019370.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2010-05-284984
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
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  • 5
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    Monoclonal B-cell lymphocytosis in healthy blood donors: an unexpectedly common finding
    American Society of Hematology ; 2014
    In:  Blood Vol. 123, No. 9 ( 2014-02-27), p. 1319-1326
    Details
    In: Blood, American Society of Hematology, Vol. 123, No. 9 ( 2014-02-27), p. 1319-1326
    Abstract: The prevalence of MBL among blood donors is much higher than previously reported. Although uncommon, higher-risk MBL phenotypes and genotypes were observed.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2013-08-523704
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 6
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    Prevalence of MBL Increases Over Time In Relatives of CLL Families,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3881-3881
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3881-3881
    Abstract: Abstract 3881 Background: Chronic lymphocytic leukemia (CLL) is largely incurable neoplasm of the blood and has one of the highest familial risks of disease among cancers. Monoclonal B-cell lymphocytosis (MBL) with a CLL immunophenotypic profile (i.e., CLL-like MBL) is a precursor state to CLL. In the general adult population, the prevalence rate of MBL is 5–9% and increases with age. This is in contrast to the 13–18% rate of MBL in first-degree relatives of CLL patients from high-risk families (defined here as families with at least two confirmed living cases of CLL). Few longitudinal studies of MBL incidence exists. One study evaluated MBL status over time in a cohort of individuals with MBL from a rural valley in Northern Italy. Our work herein will be the first to evaluate the status of MBL over time in relatives of CLL patients from high-risk families. Methods: Using a cohort of 41 high-risk CLL families, we evaluated the MBL status and clonal blood B-cell counts in 94 relatives of CLL patients at two time points at least 1 year a part. High sensitivity, multi-color flow cytometry was performed on fresh or previously frozen blood samples in three laboratories: Duke University, the US Food and Drug Administration, and Mayo Clinic. The number of cell events collected for flow cytometry evaluation varied from 1 to 5 x105 cells. To assure concordance across flow cytometry laboratories, 15 samples were evaluated at multiple labs. The concordance of MBL calling was a 100%. We defined three monotypic B-cell subsets as CLL-like MBL (CD5+ CD20dim), atypical MBL (CD5+ CD20+), and non-CLL like MBL (CD5−CD20+). Results: Of the 94 relatives, the median age at consent was 57 years (range 42–93) and 39% were male. At the initial MBL screening, 70 (74%) relatives had normal immunophenotype (NIPT) and 24 (26%) had MBL (1 atypical MBL, 3 non-CLL like MBL, and 20 CLL-like MBL). Seven of the 24 individuals with MBL had monoclonal B-cell counts available at baseline screening; median = 147.4 cells/uL (range 22.7–1663). The 94 relatives underwent repeat evaluation with a median follow up time of 1.8 years (range 1–6). At the second evaluation, we found an increase in the prevalence of MBL, with 11 of the 70 (12%) initially NIPT relatives developing a new MBL clone (10 CLL-like, 1 non-CLL like). These 11 incident MBL cases were from 9 families with 2 families each having 2 relatives changing MBL status. The median number of monoclonal B-cells in these 11 incident MBL cases was 0.58 cells/uL (range 0.38–60.3). The 23 out of the 24 relatives with baseline MBL (20 CLL-like MBL and 3 non-CLL like MBL) had a persistent MBL clone. Only 6 of these 23 individuals had monoclonal B-cell counts available at both time points, and among these 6, the clonal B-cell counts decreased at follow-up screening; median difference −64.1 cells/uL (range −1204.3– 10.5). The second evaluation of the initial atypical MBL relative had too few clonal cells for flow assessment. Conclusion: We found that our CLL-like MBL clones persisted over the period of observation in relatives from high-risk CLL families; this finding is similar to that previously reported using a population-based study conducted in Northern Italy. Notably, 12% of relatives from high-risk CLL families developed incident MBL during just 2 years of follow up. Although these MBL clones are all low count ( 〈 1500 cells/uL), these data provide further evidence that MBL is a marker of inherited predisposition to CLL. It will be important to see how our rate of change of MBL status compares to that of the general population as we continue to follow our cohort of CLL families. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3881.3881
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 7
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    Monoclonal B-Cell Lymphocytosis (MBL) in Blood Donors: Age- and Sex-Specific Prevalence, Clone Size, and IGHV-IGHD-IGHJ Rearrangements
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2840-2840
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2840-2840
    Abstract: Abstract 2840 Recent studies using sensitive flow cytometry methods have reported up to 14% MBL prevalence among older adults. Although MBL has been detected in donated blood, a systematic study of MBL prevalence in blood donors is lacking. We initiated the first such study, using high sensitivity immunophenotyping and ensuring exclusion of repeat donors. Here we report results from the first ten months. Starting in May 2010, samples from 1090 blood donors over 44 years old were collected at a regional U.S. blood center. Samples were immunophenotyped by flow cytometry with a six-color antibody cocktail (CD19, CD20, CD5, CD45 and κ/λ immunoglobulin light chains). At least 500, 000 events were collected on a FACS Canto II flow cytometer. Histograms were examined for phenotypic patterns consistent with B cell clonality. Samples were classified as MBL when at least 50 clonal B cells were detected. MBL immunophenotypes were categorized into typical chronic lymphocytic leukemia (CLL)-like, atypical CLL-like, or non-CLL-like (CD5 negative). Samples from MBL cases underwent PCR amplification, and IGHV- IGHD- IGHJ gene rearrangements were sequenced when possible. The overall MBL prevalence (Table 1) was 7.7% (84/1090). The sex-specific prevalence was 4.2% in women and 10.2% in men. The prevalence increased with increasing age for men. In women the prevalence increased sharply from the 45–54 age group to the 55–64 age group. The prevalence in the 〉 64 age group of women appeared to drop, but this estimate is unreliable due to the small number of observations. Multivariate log-binomial regression modeling showed that male sex and increasing age are independent risk factors for MBL: the age-adjusted prevalence ratio for sex (men/women) was 2.3 (95%CI 1.4–3.7; p=0.001), while the sex-adjusted prevalence ratio for age group 65 and older compared to the youngest age group (45–54) was 2.1 (95%CI 1.2–3.7; p=0.006). The median absolute B-cell count was comparable in blood donors with and without MBL (167/μl vs. 160/μl). The clonal B-cell count in donors with MBL was low (median 11/μl, 10th-90th percentiles 1–122). However, the clonal count was much higher (median 333/μl, 10th-90th percentiles 90–2887) in the subset of MBL donors in whom more than 80% of the B-cells were clonal. Moreover, the clonal B-cell counts in atypical CLL-like and non-CLL-like MBL were higher (median 37/μl, n=31) than in typical CLL-like MBL (median 4/μl, n=53) (p=0.0002). Of the 84 MBL cases, 82 were PCR-amplified and examined for monoclonal bands reflecting IGHV-IGHD-IGHJ rearrangement. In the 29 samples where monoclonal banding was detected, the median clonal count was 40/μl, while it was only 8/μl in 53 samples where no monoclonal banding was detected. Of the 29 samples with monoclonal banding, 19 were heavily mutated ( 〈 97% germline), 6 minimally mutated (97–99%), and 4 unmutated (100%); 21 (72%) were IGHV3, and the remaining 8 (28%) were IGHV4 (Figure 1). CLL-related IGHV genes were uncommon. This study has so far revealed a much higher prevalence of MBL in donated blood than previously reported. The majority of MBL in this population are mutated, CLL-like, low count MBL, which has also been seen in residential population studies. These findings suggest that MBL in donated blood typically represents indolent MBL rather than clinical MBL. However, the biology of MBL is still being elucidated. Given the reported association (Castillo et al, Blood 2010) between red blood cell transfusions and non-Hodgkin lymphoma (particularly the aggregate category CLL/SLL), our findings underscore the need to ascertain long-term outcomes in recipients of blood from MBL donors. In addition, these results will be important in interpreting findings from other studies of MBL prevalence and risk factors. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2840.2840
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 8
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    All Trans Retinoic Acid (atRA) Differentiation Markers in Normal and Retinoid-Resistant Acute Promyelocytic Leukemia Cells Revealed Induction of atRA Metabolism as Relevant Prognostic of APL Sensitivity to Therapy.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 3256-3256
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 3256-3256
    Abstract: It is now well established that all trans Retinoic Acid (atRA), administered at pharmacological doses to Acute Promyelocytic Leukemia (APL) patients, provides the first example of therapy by differentiation. Clinical remission is often transient as resistance develops. Because mechanisms of installation are still unclear, gene expression changes during APL cells differentiation were identified by Serial Analysis of Gene Expression (SAGE). Construction of proliferative and 48 hours atRA-treated NB4 cells libraries allowed us to identify a set of new transcriptional markers. Expression profiles of atRA response were performed on NB4, two atRA-resistant cell lines (NB4-LR2 and UF1) and APL blasts by real time PCR analyze on Microfluidic Card. We choose a hundred genes from multiple functional classes since there are several potential mechanisms for atRA resistance: target gene expression, transcription regulation, atRA metabolism, proteasome pathways≡ Reliability between SAGE and Microfluidic technologies is high since 95% of significantly modulated SAGE transcripts (p & lt;0.01) show the same modulation by PCR. Analyzes provide valuable markers of the granulocytic phenotype (ICAM3, S100A9, CYP4F3, TMSB10), relevant and new atRA target genes (HIC1, ID2). Moreover, SAGE highlights chromatin remodeling factors, histone deacetylase (HDAC11) or coactivator (NCOA3) which may play a crucial role in the differentiation process. Finally, we insulate markers that correlate with resistance (CEBPA, CRABP2, NDRG1, CYP26). Transcriptome studies were conducted onto blast of patients with distinct long-term sensitivity, established by correlation to the in vitro differentiation rate (Cassinat, B. et al. Blood, 2001). As a result, all patients show transcriptional response to retinoid. However, once blast differentiation reached, induction of atRA-response element genes in high sensitive blasts is reduced. In opposition, transcripts expression of low sensitive patients is still high, revealing a delay in differentiation establishment. Conversely, expression of cytochrome p450 CYP26, involved in the atRA catabolism, is maintained in highly sensitive blast whereas no modulation is observed in low sensitive blast. Because promoter analysis reveals Homeobox response element, involvement of HOX factors found in SAGE librairies was investigated. In cell lines, HOX factors cooperate with retinoid receptors to increase CYP26 transcription. Furthermore, high-pressure chromatography shows a switch between atRA and its metabolites, 6 hours after atRA addition but only in sensitive cell line. To conclude, CYP26 is a relevant marker of resistance prognostic. Since metabolites show similar efficiency for cell growth inhibition and differentiation than atRA, their implication in resistance installation is investigated.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.3256.3256
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 9
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    Premonoclonal B-cell lymphocytosis: the CLL cell of origin
    American Society of Hematology ; 2022
    In:  Blood Vol. 139, No. 10 ( 2022-03-10), p. 1436-1437
    Details
    In: Blood, American Society of Hematology, Vol. 139, No. 10 ( 2022-03-10), p. 1436-1437
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2021014339
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 10
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    Investigation of CLL-Susceptibility Loci with Monoclonal B-Cell Lymphocytosis (MBL) Risk and Confirmation of Recently Reported CLL-Susceptibility Loci
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 2443-2443
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2443-2443
    Abstract: Abstract 2443 Background: There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association (GWA) study of CLL identified genetic variants located on chromosomes 2q13, 2q37.1, 6p25, 11q24, 15q23, and 19q13 that increased the risk of CLL within a European population. We replicated 5 of these 6 loci in an independent sample of CLL cases and controls from the United States. We now investigate whether these loci also influences MBL, a reported precursor condition of CLL. In addition, a follow-up analysis of the initial GWA study identified four more CLL-susceptibility loci on 2q37.3, 8q24.21, 15q21.3, and 16q24.1. Herein, we also evaluate the association of these four loci with risk of CLL. Methods: Peripheral blood samples were obtained from three ongoing studies: the Genetic Epidemiology CLL (GEC) Consortium, the Mayo Clinic non-Hodgkin lymphoma (NHL)/ CLL study, and the Mayo Clinic Biobank. We implemented rigorous genotyping quality-control measures, and successfully genotyped a total of 407 CLL patients, 965 controls, and 60 MBLs from these studies. Within each locus, the previously reported single nucleotide variants (SNPs) or variants in high linkage disequilibrium (LD) with the previously reported SNPs were evaluated with risk of MBL or CLL. Tests for association was done using the Cochran-Armitage trend test, and unconditional logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for CLL or MBL risk Results: In our evaluation of the six initially reported CLL-susceptibility loci (2q13, 2q37.1, 6p25, 11q24, 15q23, and 19q13) with MBL risk, we found three of the six had suggestive associations (p-value 〈 0.20) with ORs comparable to and in the same direction as those observed from CLL risk. Our strongest finding was with rs13397985 at locus 2q37.1 (OR= 1.56; 95% CI: 1.05, 2.31; p-trend = 0.041), followed by rs17483466 at locus 2q13 (OR= 1.49; 95% CI: 0.99, 2.24; p-trend = 0.074). As expected given our previously reported findings with CLL risk, the association between rs11083846 on chromosome 19q13 and MBL risk was not significant (p-trend = 0.70). Of the four recently reported CLL-susceptibility loci SNPs located on 2q37.3, 8q24.21, 15q21.3, and 16q24.1, we found all to be associated with CLL risk but one. Specifically, the strongest association was seen for locus 8q24.21 (best tagged SNP rs1021955; OR = 1.37; 95% CI: 1.10, 1.70; p-trend = 0.005), followed by locus 16q24.1 (best tagged SNP rs305065; OR= 0.77; 95% CI: 0.61, 0.97; p-trend = 0.024). However, we found no associations for locus 15q21.3 for the previously reported SNP nor for any SNPs in LD with the previously reported SNP. Conclusions: Our MBL results provide additional robust genetic evidence that MBL is a precursor to CLL and that it shares similar underlying genetic predisposition. Also our results confirm three of the four recently reported CLL-susceptibility loci and further support the role of a genetic basis in the etiology of CLL. More research is needed to elucidate the potential manner in which these genetic loci function in CLL or MBL. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.2443.2443
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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