Germline POT1 Variants Can Predispose to a Variety of Hematologic Neoplasms

Germline mutations in the shelterin component protection of telomeres 1 (POT1) were recently found to be associated with familial chronic lymphocytic leukemia (CLL), melanoma, glioma, and several other familial cancer syndromes. The role of POT1 mutations in myeloid neoplasms and other hematologic malignancies, however, remains unknown. To explore the role of POT1 variants in hematologic neoplasms, we analyzed POT1 variants in 3323 consecutive patients who underwent next-generation sequencing (NGS) of a panel of hematologic malignancy-associated genes at our institution and characterized the clinical and pathological characteristics of patients with germline and somatic POT1 mutations. Of 3323 consecutive patients who underwent NGS, 2770 patients had a hematologic malignancy (lymphoid n = 1299, myeloid n = 934, and both lymphoid and myeloid n = 537), while 553 patients were evaluated for non-malignant cytopenias. All 57 patients (2.06%) carrying either a POT1 disease-associated variant or variant of uncertain significance had a hematologic malignancy compared to no identified POT1 variants in 553 patients with benign cytopenias (OR = 23.5, p < 0.001), suggesting that the presence of POT1 variants was predictive of a hematologic malignancy. Of 57 patients, 33 had lymphoid malignancies, 23 had myeloid neoplasms, and 2 had a lymphoid and myeloid neoplasm (Fig 1). Patient variants were classified as germline or somatic using constitutional DNA sequencing, POT1 emergence/disappearance over time, or POT1 maintenance in remission. In the absence of these data, likely germline or likely somatic designations were made by assessing variant allele frequencies against clinical/pathologic characteristics. 18 patients (33%) were found to have germline or likely germline POT1 variants (29% and 42% in the lymphoid and myeloid malignancy groups, respectively). Another 6 patients (11%) had variants whose germline status could not be determined. Of the 17 unique germline POT1 variants, 10 were missense and located within mapped functional protein domains, while 7 were classified as predicted loss-of-function (pLOF) due to a disruption of start, premature stop, frameshift, or spice site alteration. Patients with hematological malignancies had a ~5-8x increased odds of having a germline pLOF POT1 variant compared to cancer-free individuals in the Genome Aggregation Database (gnomAD, n = 113,108 exomes, OR = 7.5, p < 0.001) or in the Penn Medicine BioBank (PMBB, n = 7877, OR = 5.0, p = 0.010), with a prevalence of 0.25% compared to 0.03% and 0.05%, respectively. Germline pLOF POT1 variants were significantly more enriched in patients with myeloid (gnomAD: OR = 6.1, p = 0.02) and lymphoid (gnomAD: OR = 9.8, p < 0.001; PMBB: OR = 6.5, p = 0.004) malignancies. In 33 patients with lymphoid malignancies and POT1 variants, the most common diagnoses were CLL/SLL (n = 21, germline n = 6, somatic n = 12), CD5- CD10- indolent B cell neoplasms (n = 4, germline n = 1, somatic n = 3), and multiple myeloma (n = 3, all somatic) (Table 1). Lymphoid malignancies with a germline POT1 variant had a relative paucity of additional mutations; in contrast, somatic POT1 variants frequently co-occurred with other mutations, most commonly with TP53 (Fig 2, n = 5, 23%). Among 23 patients with myeloid malignancies, patients with germline POT1 variants developed malignancies at a significantly younger age compared to those whose POT1 variants were somatic (median age 59.5 vs 70.5 years, p = 0.04). The most common diagnosis in patients with myeloid neoplasms carrying germline POT1 variants was MPN (germline n = 5, somatic n = 1). AML, MDS/MPN, and MDS occurred in 4, 3, and 1 patients respectively. All patients with myeloid neoplasms had additional disease-associated mutations, with the most common co-occurring variants in TET2 (n = 7), JAK2 (n = 6, co-occurring with 50% of germline POT1 myeloid variants), and NRAS (n = 6). In conclusion, this is the first comprehensive analysis of POT1 variants in an unselected hospital-based population undergoing molecular testing for variants associated with hematologic malignancies. Our results show that the presence of POT1 variants is predictive of having a hematologic neoplasm and that over 30% of POT1 variants in hematologic malignancy patients are germline. Our study expands the spectrum of POT1-associated familial neoplasms and highlights the needs for better recognition of familial hematologic cancer syndromes. Disclosures No relevant conflicts of interest to declare.

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Role of STAT3 in Immunoregulatory Function of Human Bone Marrow-Derived Mesenchymal Stem Cells.

Blood ◽

10.1182/blood.v114.22.3637.3637 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3637-3637

Author(s):

Jinsun Yoon ◽

Seoju Kim ◽

Eun Shil Kim ◽

Byoung Kook Kim ◽

Young Lee

Keyword(s):

T Cells ◽

Conflicts Of Interest ◽

Hematologic Malignancies ◽

Treg Cells ◽

Human Mscs ◽

Hematopoietic Stem ◽

The One

Abstract Abstract 3637 Poster Board III-573 The one of the best curative treatment modality in hematologic malignancies is an allogeneic hematopoietic stem cell transplantation (HSCT). However, graft-versus-host disease (GVHD) is a major obstacle of allogeneic HSCT. BM derived human MSCs are known to have immunoregulatory effect in vitro and in vivo via inhibiting alloreactive T lymphocytes, leading to their clinical use for the prevention of GVHD in HSCT. However, the molecular mechanism of immunoregulatory effect of human MSCs is not fully understood. In this study, the signaling of immunoregulatory effect was investigated by co-culture of human MSCs with lymphocytes. The proliferation of allogeneic T cells was inhibited by MSCs. Among the STATs, STAT3 was a key molecule in MLR co-cultured with MSCs. STAT3 siRNA treated MSCs did not inhibit the lymphocyte proliferation. After MSCs were trasnsfected with STAT3 plasmid, the fraction of CD4+CD25+FOXP3+ cells (Treg cells) were increased, while the fraction of CD4+, CD8+, CD25+ was decreased. In addition, Th1-related cytokines (IL-2, IL-12 and INF-γ) and Th17-related cytokines (IL-6, IL-17 and IL-21) were down-regulated, and Th2-related cytokines (GATA-3, IL-4 and IL-10) were up-regulated in MLR co-cultured with STAT3-ablated MSCs, while vice versa in MLR co-cultured with STAT3-transfected MSCs. Furthermore, ELISA showed that concentration of Th1-related cytokine (IL-2) in the supernatant of MLR co-cultured with STAT3-ablated MSCs was higher than that of control; while concentration of Th2-related cytokine (IL-4) was lower than that of control. These results suggested that induction of Th1 to Th2 shift by MSCs might be mediated via STAT3 molecule. In summary, STAT3 may be an indispensable molecule in the immunoregulatory effect in human MSCs via modulation of regulatory T cells. Disclosures: No relevant conflicts of interest to declare.

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Risk of Burkitt Lymphoma Correlates with Breadth and Strength of Antibody Response to Plasmodium Falciparum Malaria Stage-Specific Antigens

Blood ◽

10.1182/blood.v120.21.lba-3.lba-3 ◽

2012 ◽

Vol 120 (21) ◽

pp. LBA-3-LBA-3

Author(s):

Peter Aka ◽

Maria Vila ◽

Amar Jariwala ◽

Francis Nkrumah ◽

Benjamin Emmanuel ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Confidence Intervals ◽

Burkitt Lymphoma ◽

Protective Immunity ◽

Conflicts Of Interest ◽

Hematologic Malignancy ◽

Merozoite Surface Protein ◽

Blood Stage ◽

Malaria Parasites

Abstract Abstract LBA-3 The incidence of endemic Burkitt lymphoma (eBL) is high in areas where Plasmodium falciparum (Pf) malaria is endemic, which suggests a role of malaria in eBL etiology. Previous data suggest that children with eBL are 5–12 times more likely to have elevated antibody titers to the whole schizont extract, a surrogate of exposure to malaria, compared to controls of comparable age and sex without eBL. However, the corollary studies to understand the role of protective malarial antibodies in eBL have not been conducted. We hypothesized that the risk for eBL might be different according to the breadth and strength of protective immunity to clinical malaria in children exposed to Pf malaria parasites. We investigated this hypothesis in children with and without eBL cases using samples from the National Cancer Institutes (NCI) Ghana Burkitt Lymphoma Study. Cases were children aged 0–15 years enrolled at the Korle-Bu Teaching Hospital, Accra, Ghana, during 1965–1994. Controls were children enrolled contemporaneously from the same villages as the cases or children who were referred to Korle-Bu as BL but diagnosed with benign or a non-hematologic malignancy. Antibodies to recombinant Pf serine repeat antigen 36 (SE 36) and merozoite surface protein-1 (MSP-1), which are blood stage vaccine candidates, and antibodies to histidine-rich protein-II (HRP-II), an exposure antigen expressed during the blood stage, and the peptide 6NANP, which is a circumsporozoite protein (CSP) expressed in the pre-hepatic stage, were measured using sub-class-specific enzyme-linked absorbent immunoassays (ELISAs). Antibodies to tetanus toxoid were measured as an irrelevant antigen control. Markers were included if the within (W)- and between (B)-plate coefficients of variation for the sub-class-specific IgG results was <30% (Figure 1). The independent association of each malaria marker with eBL was determined by calculating the odds ratio (ORs) and 95% confidence intervals (95% CIs) using unconditional multivariable logistic regression adjusted for sex, age, calendar year, and for all the other malaria markers, which were hypothesized to be contributory. In adjusted results, eBL was inversely associated with IgG1 seropositivity to SE36 (OR 0.54 [95% CI 0.34–0.86], p=0.01) and positively associated with HRPII (OR 1.47 [95% CI 1.06–2.02], p=0.019). The ORs for eBL were significantly decreased for low, medium, and high titers, but without a trend (0.44, 0.47, and 0.58 for low, medium, and high, respectively [ptrend=0.216]) (Figure 2: Odds ratios and 95% confidence intervals of association of eBL with different malaria markers). They increased significantly with increasing titers of IgG3 antibodies to HRPII (ORs 1.83, 1.91, to 2.25 for low, medium, and high titers, respectively [ptrend<0.002]) and showed a trend. Having antibodies to 6NANP was associated with eBL (OR 1.48 [95% CI 0.90–2.43]), but among the positives, having medium and high IgG3 antibodies to 6NANP as opposed to being sero-negative was associated with decreased risk of BL (ORs 0.79 and OR 0.60, respectively [ptrend=0.002]). Models with three markers (IgG1 to SE36, IgG3 to HRP-II, and IgG3 to 6NANP) predicted eBL better than models with just one of the markers. These data suggest children with eBL in Ghana had decreased SE36 IgG1 and increased HRPII IgG3 antibodies compared to children without eBL from the same Pf endemic areas. These results fit with the hypothesis that eBL risk increases with greater exposure to Pf malaria parasites. They also provide the first confirmation of the hypothesis that antibodies elicited by antigens targeted by protective immunity might be protective for eBL. However, they also highlight that the relationship between eBL and Pf antibodies is complex as it appears to depend on whether the antibodies reflect exposure, protection, or both. A better understanding of the specific contribution of immune response to malaria in eBL risk should be the priority of efforts to discover a biomarker profile for eBL. Disclosures: No relevant conflicts of interest to declare.

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Influenza Vaccination in Patients with Hematologic Malignancies: Analysis of Practices in 200 Patients in a Single Center

Blood ◽

10.1182/blood.v112.11.4693.4693 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4693-4693

Author(s):

Florence Lachenal ◽

Catherine Sebban ◽

Mickael Duruisseaux ◽

Irène Philip ◽

Pierre Biron ◽

...

Keyword(s):

Influenza Vaccination ◽

Cell Lymphoma ◽

Hematologic Malignancy ◽

B Cell Lymphoma ◽

Hematologic Malignancies ◽

Epidemic Season ◽

Lymphoid Malignancies ◽

Mantle Cell ◽

History Of ◽

Tract Infections

Abstract Vaccination against influenza in patients with hematologic malignancies has long been a matter of clinical uncertainty. Recent studies demonstrated the immunogenicity and the tolerance of the vaccine in this population and the absence of exacerbation of the hematologic disease after vaccination. However practices are still heterogeneous and there are no established routines in France regarding the influenza vaccination of these patients. The aim of this study was to analyse vaccinal practices in a single centre and to determine clinical efficiency of the vaccination. A standardized questionnaire about influenza vaccination was filled out by 200 patients with hematologic malignancies in January, 2008 and the patients were then observed prospectively during the epidemic season to May, 2008. The median age was 58.3 (range 18–87) ; 40% of patients were older than 65 y and could benefit from a free influenza vaccine after information by social security. Most patients suffered from lymphoid malignancies (diffuse large B-cell lymphoma: 30%; follicular, marginal, lymphoplasmacytic or mantle cell lymphoma: 31.5%; multiple myeloma: 13.5%; Hodgkin’s disease:13%). The treatment was ongoing in 53.5% of cases, using aplasia-inducing chemotherapy regimens in 27.5%, rituximab in 27.5% and/or steroids in 33.5%. One quarter of patients disclosed one or several comorbidities and 14.5% had a a past medical history of autologous stem cell transplantation. Lymphopenia was present in 34.9% of cases and hypogammaglobulinemia in 21.7%. Global vaccinal rate was 25.5%; it was 16.6% among patients younger than 65 y and 38.75% among those older than 65 y. The most frequent reasons for not being vaccinated were: the vaccination was not suggested to the patients (53.7%), vaccination was contraindicated by doctors (24.2%), the patient refused the vaccine (21.5%). The main reasons for physicians for contraindicating the vaccine were: hematologic malignancy could be worsened by vaccination (33.3%), the vaccination could generate illness or asthenia (27.8%), the vaccination could not be efficient under chemotherapy (16.7%), unknown (22.2%). Half of patients who refused the vaccine were afraid of having fever; 15.5% refused because they thought that the vaccine was uselessness. Thirteen patients (6.7%) developed influenza during follow-up and 38 (19.5%) presented a significant pulmonary infection. We did not establish a significant link between the vaccination and a protection against influenza, even in specific subgroups of patients, nor between vaccination and prevention of lower respiratory tract infections. Additionnal prospective studies are thus requested. In conclusion our study revealed that the vaccination coverage could be improved in patients with hematologic malignancies. Even if we failed to demonstrate the clinical usefullness of influenza vaccination, we believe that a better knowledge by physicians of studies demonstrating its tolerance and efficiency in this population could enhance the rate of vaccination.

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Targeting CXCR4 with Cell-Penetrating Pepducins Enhances Survival in Disseminated Lymphoma

Blood ◽

10.1182/blood.v118.21.4244.4244 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4244-4244

Author(s):

Lidija Covic ◽

Katie M O’Callaghan ◽

Nga Ngyen ◽

Hsieh Mo-Ying ◽

Andreas K. Klein ◽

...

Keyword(s):

Conflicts Of Interest ◽

Apoptotic Cell ◽

Hematologic Malignancies ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Intracellular Loop ◽

Hematopoietic Stem ◽

Lymphoid Malignancies ◽

Cell Penetrating ◽

New Treatment

Abstract Abstract 4244 The G-protein coupled receptor, CXCR4, which normally regulates interactions between stroma and hematopoietic stem cells in the bone marrow, is highly expressed on a variety of malignant hematological cells, such as lymphoma and lymphocytic leukemia cells. A new treatment concept has arisen that CXCR4 may be an effective therapeutic target as an adjunct to standard clinical treatments of hematologic malignancies. In this study we developed novel cell-penetrating lipopeptide antagonists of CXCR4, called pepducins, to interdict signaling to intracellular G-proteins in response to the CXCR4 ligand, SDF-1. We demonstrated that pepducins targeting the first (i1) or third (i3) intracellular loop of CXCR4 completely abrogated SDF-1-mediated chemotaxis of lymphocytic leukemia and lymphoma cell lines, as well as primary cells isolated from patients with chronic lymphocytic leukemia. Pepducins enhanced apoptotic cell death in lymphoma and primary leukemia cells when used in combination with the CD20-targeted antibody, rituximab. Furthermore, pepducin treatment significantly increased survival both as monotherapy and in combination with rituximab in mice with disseminated lymphoma. Together, these data demonstrate that CXCR4/SDF-1 signaling is effectively inhibited by cell-penetrating pepducins, suggesting that these lipopeptide antagonists may represent a potentially new treatment strategy for lymphoid malignancies. Disclosures: No relevant conflicts of interest to declare.

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Management Of PICC-Associated Thrombosis In Patients Receiving Chemotherapy For Hematologic Malignancies

Blood ◽

10.1182/blood.v122.21.5000.5000 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5000-5000

Author(s):

Meera Sridharan ◽

Aref Al-Kali ◽

Aneel A. Ashrani ◽

Kebede Begna ◽

Michelle Elliott ◽

...

Keyword(s):

Platelet Count ◽

Conflicts Of Interest ◽

Hematologic Malignancy ◽

Superior Vena ◽

Vena Cava ◽

Hematologic Malignancies ◽

Limited Information ◽

Jugular Veins ◽

Increased Risk

Abstract Background Tunneled central venous catheters have traditionally been used for administration of chemotherapy (chemo) for acute leukemia treatment. Peripherally inserted central catheters (PICC) are increasingly being used, but there is an increased risk of PICC-associated thrombosis (PAT). There is limited information on management of PAT in this subgroup of patients (pt). Methods In this retrospective cohort study we investigated the primary management of PICC related upper extremity venous thrombosis (TB) in pt with hematologic malignancy undergoing chemo at Mayo Clinic Rochester. Eligible pt were 18 years and older, had documentation of PICC placement at our institution, initiation of chemo within a week of PICC placement, and the TB was objectively documented by compression venous ultrasound (CVU). Superficial venous TB (SVT) was defined as TB of subcutaneous veins (basilic and cephalic) and deep venous TB (DVT) defined as TB of brachial, axillary, subclavian, or innominate superior vena cava and internal jugular veins. We retrospectively stratified initial management (IM) into 1) PICC removal alone (PR), 2) PR and therapeutic anticoagulation (AC), 3) AC alone, and 4) conservative management (CM) consisting of symptomatic care and observation. We also investigated factors influencing IM of PAT. Long term outcomes including incidence of pulmonary embolism (PE), post phlebitic syndrome and recurrence of TB were noted. Results Between 2006 and 2012, 190 pt with AML (n=160), MDS or MDS/MF (n=10), or ALL (n=20) met our study criteria. Overall, 40/190 (21.6%) developed PAT: AML n=38, ALL n=1, MDS/MF n=1. SVT occurred in 16/40 (40%) pt and DVT occurred in 24/40 (60%) pt. IM is shown in Table 1. One pt with SVT received AC for 6 weeks as well as PR. In this pt, IM included AC because of proximity of TB to deep veins. 7 pt had a follow up (f/u) CVU within 3 months demonstrating: TB progression (prog, n=1, IM with PR alone but with prog AC was started); TB stability (stab, n=2, both IM with PR alone) and TB resolution/improvement (R/I, n= 4, 2 IM with PR and 2 IM with CM) In the 5 pt with CM, 2 pt had f/u CVU demonstrating improvement, one pt had charted clinical improvement , and 2 pt had no charted clinical f/u. Of DVT pt on AC (n=14), 5 pt completed at least 2 months of AC. Reasons for early cessation (n=9) of AC included thrombocytopenia (tcp, n=4), hematoma (n=1), hematuria (n=1), subarachnoid hemorrhage (n=1), and unknown (n=1). One pt died 2 days after presence of DVT was noted. Two pt initially treated with PR alone developed a second TB with placement of a new PICC on contralateral arm and AC was subsequently initiated (duration: 3 months (n=1), and 8 days (n=1)). 14 pt with DVT had f/u CVU within 3 months which demonstrated prog (n=2), stab (n= 8), or R/I ( n=4) of TB (Table 2). The 2 pt with TB prog subsequently received longer term AC guided by platelet count. In 5 pt with PICC not initially removed, 3 pt had PR after completion of chemo. (1-4 days), one pt had PR at discharge (27 days from TB), and one pt had PICC in place on discharge. One pt with DVT experienced a PE within one year f/u. This pt had initially completed 3 days of AC which was stopped because of tcp. Conclusion In this cohort of patients with PAT, the most common IM consisted of PR, which appeared to result in a low recurrence rate among pt with SVT. In pt with DVT, the role of AC remains to be defined given the abbreviated course of AC in most pt. Though, the lack of CVU followup in all pt limits conclusions, there appeared to be a low rate of symptomatic prog. Initiation of AC was largely guided by platelet count and degree of occlusive symptoms. Thrombocytopenia was also the most commonly cited reason for discontinuing AC. Close clinical follow up aided by the use of CVU was integral to ensure that PAT did not lead to further adverse events. Disclosures: No relevant conflicts of interest to declare.

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ANCA-Associated Vasculitides and Hematologic Malignancies: Lessons from the Past and Future Perspectives

Journal of Immunology Research ◽

10.1155/2019/1732175 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Marco Folci ◽

Giacomo Ramponi ◽

Dana Shiffer ◽

Aurora Zumbo ◽

Michele Agosti ◽

...

Keyword(s):

Granulomatosis With Polyangiitis ◽

Hematologic Malignancy ◽

Hematologic Malignancies ◽

Future Perspectives ◽

The Past ◽

Anca Associated Vasculitis ◽

Uncommon Presentation ◽

Immunotherapy Target ◽

And Function

The purpose of this paper is to collect and summarize all evidences relating to an association between ANCA-associated vasculitides (AAVs) and hematologic malignancies, in the form of either a paraneoplastic vasculitis or leukemias and lymphomas developing on a preexisting vasculitis. Additionally, the role of cyclophosphamide in vasculitis treatment has been assessed and compared to rituximab. Paraneoplastic AAV seems to be an uncommon presentation of hemopathies. Hematologic malignancy risk in AAV is more likely to be increased by cyclophosphamide, although not yet definitely proven. Furthermore, the pathogenesis of ANCA-associated vasculitis has been reviewed with particular emphasis on the role of proteinase 3 (PR3) in fuelling granulomatosis with polyangiitis (GPA) inflammation. PR3 is a bactericidal protein expressed by neutrophilic granules and on their plasma membrane. Derangements in its expression and function have been linked to leukemias and GPA alike. PR3-derived PR1 peptide is being studied as an immunotherapy target in leukemia and multiple myeloma. This study is aimed at bringing together various evidences from the field of immunological and hematological research, at exposing contradictions, and at revealing novel insights on the association between ANCA-associated vasculitis and hematologic malignancies.

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Lymphoproliferative Conditions of the Serosa

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2011-0150-sa ◽

2012 ◽

Vol 136 (3) ◽

pp. 268-276 ◽

Cited By ~ 7

Author(s):

Richard Attanoos

Keyword(s):

Clinical Outcomes ◽

Plasma Cell ◽

Hematologic Malignancy ◽

Hematologic Malignancies ◽

Lymphoproliferative Disease ◽

Data Sources ◽

Lymphoproliferative Diseases ◽

Complex Variety ◽

Extranodal Disease

Context.—A diverse and complex variety of lymphoproliferative diseases may involve the serosa, with widely differing clinical outcomes encompassing a spectrum of benign and malignant conditions. Objective.—To review lymphoproliferative disease involving the serosa and to provide a practical approach to the evaluation of lymphoid and plasma cell infiltrates in the serosa, together with a review of various tumors and tumorlike conditions that may mimic lymphoproliferative disease. Data Sources.—Analysis of published literature. Conclusions.—All forms of hematologic malignancy may involve the various serosal sites, although this is usually observed as secondary involvement in persons with known lymph nodal, marrow-based, or extranodal disease. Primary pericardial, pleural, and peritoneal lymphomas are rare; many nonneoplastic conditions may mimic lymphoma and a variety of nonhematolymphoid tumors may simulate hematologic malignancies. An understanding of the role of ancillary tests, together with an appreciation of their limitations, will prevent misdiagnosis.

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Suppression of Mir-708 Promotes DKK3 to Inhibit Wnt/β-Catenin Signaling Pathway in Adult B-ALL

Blood ◽

10.1182/blood.v128.22.5090.5090 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5090-5090

Author(s):

Yingjie Zhang ◽

Huibo Li ◽

Rongyi Cao ◽

Lili Sun ◽

Yan Wang ◽

...

Keyword(s):

Signaling Pathway ◽

Solid Tumors ◽

Conflicts Of Interest ◽

Hematologic Malignancies ◽

Leukemia Cells ◽

Childhood All ◽

Apoptosis Inhibition ◽

Low Levels ◽

Matched Samples

Abstract Dickkopf-3 (DKK-3) is a Wnt signaling antagonist, and DKK3 inactivation is associated with poor prognosis in various solid tumors and hematologic malignancies. Epigenetic hypermethylation has been implicated in downregulation of DKK3, but other regulatory mechanisms remain to be investigated. In this study, we examined DKK3 expression and the role of microRNA in the regulation of DKK3 in adult B-ALL. Our results showed low levels of DKK3 expression in Nalm-6 and BALL-1 cell lines, and leukemia cells from adult B-ALL patients. DKK3 expression was remarkably lower in the initial diagnosis and relapse samples than in the matched samples during remission. In addition to hypermethylation, low levels of DKK3 were associated with high expression of miR-708. This finding was similar to that in childhood ALL. The miR-708 was predicted to bind to the 3'-UTR of DKK3. By using miR-708 mimics, we found that miR-708 targets DKK3 to promote B-ALL cell proliferation through cell cycle promotion and apoptosis inhibition. The treatment with 5-aza-2'-deoxycytidine significantly increased DKK3 and decreased p-GSK3β, cyclin D1 and nuclear and cytoplasmic β-catenin protein expression. A synergistic effect was seen when the miR-708 inhibitor and 5-aza were used simultaneously. Although miR-708 was reported to either promote or suppress tumorigenecity in some solid tumors, our findings indicate that suppression of miR-708 increases DKK3 expression to inhibit the Wnt/β- catenin signaling pathway in B-ALL. Disclosures No relevant conflicts of interest to declare.

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Vitamins, Minerals, and Specialty Supplements and Risk of Hematological Malignancies In the VITamins and Lifestyle (VITAL) Cohort Study

Blood ◽

10.1182/blood.v116.21.4143.4143 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4143-4143

Author(s):

Filippo Milano ◽

Roland B. Walter ◽

Theodore M. Brasky ◽

Emily White

Keyword(s):

Folic Acid ◽

Dietary Supplements ◽

Hematological Malignancies ◽

Conflicts Of Interest ◽

Hematologic Malignancy ◽

Hematologic Malignancies ◽

Cox Proportional Hazards ◽

Case Control Studies ◽

History Of ◽

Incident Cases

Abstract Abstract 4143 Introduction: The use of vitamins and dietary supplements is a common health practice in many parts of the world, in part because of the belief that they will prevent diseases, including cancer. However, results of epidemiologic studies regarding their efficacy in reducing the risk of any cancer, particularly hematologic malignancies, are inconsistent and are mostly limited to case-control studies. Materials: Participants were male and female members of the VITamins And Lifestyle (VITAL) cohort. Between 2000 and 2002, 64,839 men and women, aged 50 to 76 years, who lived in the region of Washington State covered by the Surveillance, Epidemiology, and End Results (SEER) registry, were recruited. Participants were excluded if they had any cancer prior to baseline other than non-melanoma skin cancer and were censored at the time of diagnosis of a non-hematologic malignancy during follow-up; after exclusions, there were 64,839 participants available for study. Incident cases of hematologic malignancies were identified through December 2008 by linkage to the SEER registry. Participants answered questions on the frequency (days/week), duration (years), and dose per day of their supplemental use of vitamins, including A, B3, B6, B12, C, D, E, multivitamin compounds, and folic acid; minerals, including calcium, selenium, iron, magnesium, chrome, and zinc during the 10 years before baseline. For the non-vitamin, non-mineral “specialty” supplements, garlic, ginseng, and fish oil, only frequency and duration were ascertained. Use of vitamin and mineral supplements was categorized into non-users and tertiles of use, such that the highest category was greater than could be achieved only by use of a common multivitamin (Centrum Silver). 10-year average use of specialty supplements was categorized into: non-user; low use, <4 days/week or <3 years; and high use, ≥4 days/week and ≥3 years. Multivariable-adjusted Cox proportional hazards models were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CI) of the use of dietary supplements with the risk of total hematologic malignancies. Models were adjusted for age, sex, race/ethnicity (white/hispanic/other), education, smoking, self-rated health, physical activity, history of anemia in the year before baseline, and family history of leukemia or lymphoma. Results: A total of 577 case of hematological malignancies were identified including MDS [n=54], AML [n=36], myeloproliferative disorders [n=46], CLL/SLL [n=88] and other non-Hodgkin lymphomas [n=235], Hodgkin lymphomas [n=22], plasma cell disorders [n=66], mature NK/T cell neoplasms [n=17], and other entities [n=13]). None of the vitamin 10-year average intakes were associated with decreased risk of incident hematologic malignancies There was no evidence that high use of vitamins A (HR=0.79, 95% CI: 0.58–1.08; p-trend=0.28), B12 (HR=0.98, 95%CI: 0.73–1.31; p-trend=0.26), C (HR=0.97, 95% CI: 0.77–1.22; p-trend=0.99), D (HR=0.90, 95% CI: 0.62–1.31; p-trend=0.45), or folic acid (HR=1.00, 95% CI: 0.73–1.39; p-trend=0.19) was associated with the risk of blood cancer. Among specialty supplements, only high 10-year average use of garlic was significantly associated with a reduced risk of development of blood cancers (HR=0.64,95% CI: 0.42–0.98); however the association was not linear (p-trend=0.14). Conclusions: We observed no reduction in the risk of incident hematologic malignancies with dietary supplement and vitamin use with the exception of garlic when used at a high amount (≥4 days/week for ≥ 3 years). Disclosures: No relevant conflicts of interest to declare.

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Non-AIDS-Defining Hematologic Malignancies in HIV-Infected Patients: A Nationwide Epidemiologic Study in Japan

Blood ◽

10.1182/blood.v118.21.2183.2183 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2183-2183

Author(s):

Shotaro Hagiwara ◽

Mihoko Yotsumoto ◽

Seiji Okada

Keyword(s):

Complete Remission ◽

Hiv Infection ◽

Highly Active Antiretroviral Therapy ◽

Conflicts Of Interest ◽

Hematologic Malignancy ◽

Epidemiologic Study ◽

Fold Increase ◽

Hematologic Malignancies ◽

The Mean ◽

Hodgkin's Lymphomas

Abstract Abstract 2183 Background. The prevalence of HIV infection is estimated to be less than 0.1% in Japan; however, the number of newly reported HIV-infected persons has gradually increased, and the estimated number of HIV-infected patients now ranges from 6300 to 10000. Since the introduction of highly active antiretroviral therapy (HAART), the morbidity and incidence of AIDS-defining cancers has decreased. However, the incidence of non-AIDS-defining cancers has increased in Japan. To elucidate the incidence and clinical outcome of non-AIDS-defining hematologic malignancies, excluding non-Hodgkin's lymphomas, in HIV-infected patients, we conducted a nationwide epidemiologic study. Methods. We surveyed 429 regional AIDS centers and 497 educational hospitals certified by the Japanese Society of Hematology. Epidemiologic data for HIV was sourced from the Joint United Nations program on HIV/AIDS. Results. We obtained data from 511 institutes (55.4%). From 1991 to 2010, 47 cases of non-AIDS-defining hematologic malignancies were found—19 cases of Hodgkin's lymphoma (HD), 13 of AML, 7 of ALL, 4 of CML, 2 of multiple myeloma, 1 of CLL, and 1 of MDS-RAEB1. The mean age was 49.3 years (21–70 years), and 93.6% patients were male. The mean CD4-positive cell count was 303.7/μL (1–1371/μL). The mean duration from the diagnosis of HIV infection to hematologic malignancy was 45.0 months (0–204 months). Before diagnosis, 68.1% patients had been treated with HAART and 51.1% patients had AIDS. Sixteen of 19 HD patients were treated with ABVD or radiation therapy. Of these, 80% patients achieved complete remission, with a 2-year overall survival of 62.3%. Twelve of AML and 6 of ALL patients were treated with standard induction chemotherapy. Eight of twelve patients (66.7%) with AML and five of six patients (83.3%) achieved complete remission. The median survival for both AML and ALL patients was 16 months, with 42.8% ALL and 30.8% AML patients alive after 4 years. Comparison of the last 2 decades (1991–2000 and 2001–2010) showed a 4.7-fold increase in the incidence of hematologic malignancies (11.5 vs. 54.6/100000 person-years). Conclusion. A nationwide epidemiologic study revealed that HIV-infected patients are at high risk of hematologic malignancies, and that the incidence of hematologic malignancies has increased in the past decade. The prognosis was equivalent to that of HIV-negative patients, and standard chemotherapy may be a feasible treatment option for HIV-infected patients with hematologic malignancies. Disclosures: No relevant conflicts of interest to declare.

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