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Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target.

La, 21/04/2018 - 14:20
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Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target.

Nat Commun. 2018 Apr 19;9(1):1567

Authors: Dufva O, Kankainen M, Kelkka T, Sekiguchi N, Awad SA, Eldfors S, Yadav B, Kuusanmäki H, Malani D, Andersson EI, Pietarinen P, Saikko L, Kovanen PE, Ojala T, Lee DA, Loughran TP, Nakazawa H, Suzumiya J, Suzuki R, Ko YH, Kim WS, Chuang SS, Aittokallio T, Chan WC, Ohshima K, Ishida F, Mustjoki S

Abstract
Aggressive natural killer-cell (NK-cell) leukemia (ANKL) is an extremely aggressive malignancy with dismal prognosis and lack of targeted therapies. Here, we elucidate the molecular pathogenesis of ANKL using a combination of genomic and drug sensitivity profiling. We study 14 ANKL patients using whole-exome sequencing (WES) and identify mutations in STAT3 (21%) and RAS-MAPK pathway genes (21%) as well as in DDX3X (29%) and epigenetic modifiers (50%). Additional alterations include JAK-STAT copy gains and tyrosine phosphatase mutations, which we show recurrent also in extranodal NK/T-cell lymphoma, nasal type (NKTCL) through integration of public genomic data. Drug sensitivity profiling further demonstrates the role of the JAK-STAT pathway in the pathogenesis of NK-cell malignancies, identifying NK cells to be highly sensitive to JAK and BCL2 inhibition compared to other hematopoietic cell lineages. Our results provide insight into ANKL genetics and a framework for application of targeted therapies in NK-cell malignancies.

PMID: 29674644 [PubMed - in process]

AlloHSCT for inv(3)(q21;q26)/t(3;3)(q21;q26) AML: a report from the acute leukemia working party of the European society for blood and marrow transplantation.

La, 21/04/2018 - 02:20
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AlloHSCT for inv(3)(q21;q26)/t(3;3)(q21;q26) AML: a report from the acute leukemia working party of the European society for blood and marrow transplantation.

Bone Marrow Transplant. 2018 Apr 18;:

Authors: Halaburda K, Labopin M, Houhou M, Niederwieser D, Finke J, Volin L, Maertens J, Cornelissen JJ, Milpied N, Stuhler G, Kröger N, Esteve J, Mohty M, Nagler A

Abstract
Acute myeloid leukemia with inv(3)(q21;q26.2)/t(3;3)(q21;q26.2) (3q26 AML) is a rare disease with poor prognosis and median survival of <1 year. To evaluate allogeneic stem cell transplantation (alloHSCT) in the treatment of 3q26 AML, we studied 98 patients reported to the European Society for Blood and Marrow Transplantation between 1995 and 2013. Majority of patients were transplanted using peripheral blood, from unrelated donors and after myeloablative conditioning. Fifty-three patients were transplanted with active disease and 45 in complete remission. After a median follow-up of 47 months, 2 year leukemia-free survival (LFS), overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), and graft-versus-host disease-free, relapse-free survival (GRFS) probabilities were 20%, 26%, 64%, 16%, and 14%, respectively. Two-year LFS and OS probabilities for patients transplanted in CR vs. those transplanted in active disease were 23.8 vs. 17% (p = NS) and 34.9 vs. 18.9% (p = NS), respectively. In multivariate analysis CR was the only factor associated with a trend for better LFS (p = 0.05, HR 0.64) and OS (p = 0.06, HR 0.65). CR also significantly influenced GRFS (p = 0.01; HR 0.55) and NRM (p = 0.02; HR 0.27). The results suggest that a proportion of patients might benefit from the procedure, especially if performed in CR.

PMID: 29670208 [PubMed - as supplied by publisher]

Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma; univariate and functionally-informed multivariate analyses.

To, 19/04/2018 - 14:20
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Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma; univariate and functionally-informed multivariate analyses.

Int J Cancer. 2018 Apr 18;:

Authors: Vermeulen R, Saberi Hosnijeh F, Bodinier B, Portengen L, Liquet B, Garrido-Manriquez J, Lokhorst H, Bergdahl IA, Kyrtopoulos SA, Johansson AS, Georgiadis P, Melin B, Palli D, Krogh V, Panico S, Sacerdote C, Tumino R, Vineis P, Castagné R, Chadeau-Hyam M, EnviroGenoMarkers consortium

Abstract
Recent prospective studies have shown that dysregulation of the immune system may precede the development of B-cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case-control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years prior to diagnosis (range, 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma) and matched controls. Linear mixed models, and Partial Least Square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes, and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor-2 (FGF-2, p=7.2x10-4 ) and transforming growth factor alpha (TGF-α, p=6.5x10-5 ) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p=7.8x10-7 ), TGF-α (p=4.08x10-5 ), fractalkine (p=1.12x10-3 ), monocyte chemotactic protein-3 (p=1.36x10-4 ), macrophage inflammatory protein 1-alpha (p=4.6x10-4 ), and vascular endothelial growth factor (p=4.23x10-5 ). Our results also provided marginal support for already reported associations between chemokines and diffuse large B-Cell lymphoma (DLBCL), and cytokines and chronic lymphocytic leukemia (CLL). Case-only analyses showed that GM-CSF levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth-factors in the incidence of MM, and of chemokine and cytokine regulation in DLBCL and CLL. This article is protected by copyright. All rights reserved.

PMID: 29667176 [PubMed - as supplied by publisher]

Plasma immunoprofiling of patients with high-risk diffuse large B-cell lymphoma: a Nordic Lymphoma Group study.

To, 19/04/2018 - 14:20
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Plasma immunoprofiling of patients with high-risk diffuse large B-cell lymphoma: a Nordic Lymphoma Group study.

Blood Cancer J. 2016 11 18;6(11):e501

Authors: Pauly F, Fjordén K, Leppä S, Holte H, Björkholm M, Fluge Ø, Møller Pedersen L, Eriksson M, Isinger-Ekstrand A, Borrebaeck CA, Jerkeman M, Wingren C

PMID: 27858932 [PubMed - indexed for MEDLINE]

Refined graft-versus-host disease/relapse-free survival in transplant from HLA-identical related or unrelated donors in acute myeloid leukemia.

Ke, 18/04/2018 - 14:19
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Refined graft-versus-host disease/relapse-free survival in transplant from HLA-identical related or unrelated donors in acute myeloid leukemia.

Bone Marrow Transplant. 2018 Apr 16;:

Authors: Battipaglia G, Ruggeri A, Labopin M, Volin L, Blaise D, Socié G, Tabrizi R, Cornelissen JJ, Ghavamzadeh A, Huynh A, Wu D, Yakoub-Agha I, Maertens J, Chevallier P, Mohty M, Nagler A

Abstract
Refined graft-versus-host disease (GVHD)/relapse-free survival (GRFS) considers main outcomes of allogeneic stem cell transplant (HSCT), estimating long-term survival without significant morbidity as a surrogate of HSCT success. We compared GRFS in 5059 adults with acute myeloid leukemia (AML), undergoing HSCT in first complete remission from 2000 to 2015 either from a matched sibling (MSD, n = 3731) or unrelated donor (MUD, n = 1328). Median age was 49 (range: 18-76) years. Median follow-up was 32 and 60 months in MSD and MUD, respectively (p < 0.01). Compared to MSD, at 4 years, MUD recipients had lower GRFS, with higher NRM, grade III-IV acute GVHD, and extensive chronic GVHD (HR: 1.42, p < 0.01). We also performed a risk factor analyses, showing unfavorable cytogenetics (HR: 1.42, p < 0.01) and peripheral blood as stem cell source (HR: 1.22, p < 0.01) associated to lower GRFS, while this was higher with in vivo T-cell depletion (TCD, HR: 0.73, p < 0.01) and shorter time from diagnosis to HSCT (HR 0.96, p < 0.01). Different factors, modifiable or not, such as donor type, stem cell source, disease biology, and in vivo TCD, impact on GRFS and this may guide in the future transplant choices to improve morbidity and long-term quality of life.

PMID: 29662244 [PubMed - as supplied by publisher]

Thromboembolism in Acute Lymphoblastic Leukemia: Results of NOPHO ALL2008 Protocol Treatment in Patients 1-45 Years.

Ke, 18/04/2018 - 14:19
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Thromboembolism in Acute Lymphoblastic Leukemia: Results of NOPHO ALL2008 Protocol Treatment in Patients 1-45 Years.

Blood. 2018 Apr 16;:

Authors: Rank CU, Toft N, Tuckuviene R, Grell K, Nielsen OJ, Frandsen TL, Marquart HVH, Albertsen BK, Tedgård U, Hallböök H, Ruud E, Jarvis KB, Quist-Paulsen P, Huttunen P, Wartiovaara-Kautto U, Jónsson ÓG, Trakymiene SS, Griškevičius L, Saks K, Punab M, Schmiegelow K

Abstract
Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during treatment of 1772 consecutive Nordic/Baltic ALL patients 1-45years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (7/2008-4/2017). The 2.5-year cumulative incidence of thromboembolism (N=137) was 7.9% (95% confidence interval (CI) 6.6-9.1); higher in patients ≥10years (P<.0001). Adjusted hazard ratios (HRa) were associated with greater age (10.0-17.9years: HRa 4.9, CI 3.1-7.8, P<.0001; 18.0-45.9years: HRa 6.06, CI 3.65-10.1, P<.0001) and mediastinal mass at ALL diagnosis (HRa 2.1, CI 1.0-4.3, P=.04). In a multiple absolute risk regression model addressing three thromboembolism risk factors, age ≥10years had the largest absolute risk ratio (RRage 4.7, CI 3.1-7.1; RRenlarged lymph nodes 2.0, CI 1.2-3.1; RRmediastinal mass 1.6, CI 1.0-2.6). Patients 18.0-45.9years had an increased hazard of pulmonary embolism (HRa 11.6, CI 4.02-33.7, P<.0001) and patients 10.0-17.9years had an increased hazard of cerebral sinus venous thrombosis (HRa 3.3, CI 1.5-7.3, P=.003) compared with children <10.0years. Asparaginase was truncated in 38/128 patients with thromboembolism, while thromboembolism diagnosis was unassociated with increased hazard of relapse (P=.6). Five deaths were attributable to thromboembolism, and patients <18.0years with thromboembolism had increased hazard of dying compared with same aged patients without thromboembolism (both P≤.01). In conclusion, patients ≥10years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age ≥10years, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.

PMID: 29661787 [PubMed - as supplied by publisher]

Bloodstream infections in acute myeloid leukemia patients treated according to the Finnish Leukemia Group AML-2003 protocol - a prospective nationwide study.

Ke, 18/04/2018 - 14:19
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Bloodstream infections in acute myeloid leukemia patients treated according to the Finnish Leukemia Group AML-2003 protocol - a prospective nationwide study.

Infect Dis (Lond). 2017 Nov - Dec;49(11-12):799-808

Authors: Kolonen A, Sinisalo M, Huttunen R, Syrjänen J, Aittoniemi J, Huhtala H, Sankelo M, Rintala H, Räty R, Jantunen E, Nousiainen T, Säily M, Kauppila M, Itälä-Remes M, Ollikainen H, Rauhala A, Koistinen P, Elonen E, Finnish Leukemia Group

Abstract
BACKGROUND: Infections greatly influence the outcome of acute myeloid leukemia (AML) patients receiving intensive treatment. The aim of this study was to establish the incidence, microbial etiology, risk factors and prognosis of bloodstream infections (BSIs) in patients with AML and compare the results with the previous treatment protocol (AML-92).
METHODS: Registery data were gathered prospectively from 357 patients aged 16-65 years recruited on the AML-2003 treatment protocol between November 2003 and November 2011 during different treatment cycles.
RESULTS: Blood culture data were available on 977 treatment episodes, in which there were 503 BSIs (51%). The overall incidence rate (IR) for BSIs (per 1000 hospital days) was 16.7. Twenty patients (5.6%) died due to an infection and 16 of them (80%) had a BSI. The most commonly detected microbes (polymicrobial episodes included) in blood cultures were coagulase-negative staphylococci (CoNS, 24.7%), viridans group streptococci (VGS, 19.1%), enterococci (13.9%) and Enterobacteriacae group (25.9%). The etiology of BSIs varied greatly from treatment cycle to cycle.
CONCLUSIONS: Enterococcal BSIs have increased compared to our previous treatment protocol, and they represent significant pathogens in blood cultures. Infection-related mortality has decreased despite the increase in the IR of BSIs. Enterococci seem to be an increasingly prominent pathogen underlying BSIs in the AML patients, especially during induction therapy (20%).

PMID: 28683646 [PubMed - indexed for MEDLINE]

Natural IgM antibodies in the immune defence against neoehrlichiosis.

Ke, 18/04/2018 - 14:19
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Natural IgM antibodies in the immune defence against neoehrlichiosis.

Infect Dis (Lond). 2017 Nov - Dec;49(11-12):809-816

Authors: Wennerås C, Goldblatt D, Zancolli M, Mattsson M, Wass L, Hörkkö S, Rosén A

Abstract
BACKGROUND: Neoehrlichiosis is an infectious disease caused by the tick-borne bacterium "Candidatus Neoehrlichia mikurensis". Splenectomy and rituximab therapies are risk factors for severe neoehrlichiosis. Our aim was to examine if neoehrlichiosis patients had low levels of natural IgM antibodies and/or were hypogammaglobulinemic, and if such deficiencies were associated with asplenia and vascular complications.
METHODS: Neoehrlichiosis patients (n = 9) and control subjects (n = 10) were investigated for serum levels of IgG, IgA, and IgM, and for levels of natural IgM antibodies to pneumococcal polysaccharides (6B, 14), and to the malondialdehyde acetaldehyde epitope of oxidized LDL. The multivariate method Projection to Latent Structures was used to analyze the data.
RESULTS: The levels of natural IgM antibodies of various specificities were decreased or not measurable in half of the studied patients with neoehrlichiosis. Only one patient and one control subject were hypogammaglobulinemic. An inverse relationship was noted between the levels of natural IgM antibodies and the development of deep vein thrombosis. Unexpectedly, no association was seen between having or not having a spleen and the levels of natural IgM antibody levels in the circulation.
CONCLUSIONS: Neither hypogammaglobulinemia nor lack of natural IgM antibodies alone predisposes for severe neoehrlichiosis. The importance of the spleen in the immune defence against Ca. N. mikurensis probably lies in its capacity to generate or maintain specific antibodies.

PMID: 28682152 [PubMed - indexed for MEDLINE]

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms.

Ke, 18/04/2018 - 02:19
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Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms.

Proc Natl Acad Sci U S A. 2017 01 17;114(3):E327-E336

Authors: Guo MH, Nandakumar SK, Ulirsch JC, Zekavat SM, Buenrostro JD, Natarajan P, Salem RM, Chiarle R, Mitt M, Kals M, Pärn K, Fischer K, Milani L, Mägi R, Palta P, Gabriel SB, Metspalu A, Lander ES, Kathiresan S, Hirschhorn JN, Esko T, Sankaran VG

Abstract
Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.

PMID: 28031487 [PubMed - indexed for MEDLINE]

A phase III study of lenalidomide maintenance after debulking therapy in patients with advanced cutaneous T-cell lymphoma - EORTC 21081 (NCT01098656): results and lessons learned for future trial designs.

La, 14/04/2018 - 02:18
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A phase III study of lenalidomide maintenance after debulking therapy in patients with advanced cutaneous T-cell lymphoma - EORTC 21081 (NCT01098656): results and lessons learned for future trial designs.

Eur J Dermatol. 2017 Jun 01;27(3):286-294

Authors: Bagot M, Hasan B, Whittaker S, Beylot-Barry M, Knobler R, Shah E, Marreaud S, Morris S, Dalle S, Servitje O, Cowan R, Väkevä L, Chaby G, Jonak C, Fox CP, Ritchie D, Vermeer MH, Stadler R, Romero PLO, Scarisbrick J, Quaglino P

Abstract
EORTC 21081 was a randomized phase III study of observation alone versus lenalidomide maintenance (25 mg po for 21 days) after debulking therapy in patients with advanced-stage cutaneous T-cell lymphomas (CTCLs). The aim was to investigate whether maintenance treatment with lenalidomide prolonged response after debulking in patients who had not been previously treated with intravenous chemotherapy. A total of 26 centres from 10 different European countries registered 30 patients with advanced CTCL. Twenty-one patients were randomized (20% of the 105 patients initially deemed necessary for the study; the study was terminated early following withdrawal of funding support from Celgene). Of 30 registered patients, nine failed to be randomized, 12 were randomized to observation alone, and nine to lenalidomide maintenance. Median progression-free survival was 5.3 months (95% CI: 1.87-22.54) in the maintenance lenalidomide group and two months (95% CI: 0.92-7.82) in the observation alone group. Although statistical comparison in the study was severely underpowered and would not be meaningful, this study provides useful information, revealing rapid disease progression within four weeks in a third of patients, highlighting the need for maintenance therapy.

PMID: 28468739 [PubMed - indexed for MEDLINE]

The Burden of Cardiovascular Diseases Among US States, 1990-2016.

To, 12/04/2018 - 14:16

The Burden of Cardiovascular Diseases Among US States, 1990-2016.

JAMA Cardiol. 2018 Apr 11;:

Authors: Global Burden of Cardiovascular Diseases Collaboration, Roth GA, Johnson CO, Abate KH, Abd-Allah F, Ahmed M, Alam K, Alam T, Alvis-Guzman N, Ansari H, Ärnlöv J, Atey TM, Awasthi A, Awoke T, Barac A, Bärnighausen T, Bedi N, Bennett D, Bensenor I, Biadgilign S, Castañeda-Orjuela C, Catalá-López F, Davletov K, Dharmaratne S, Ding EL, Dubey M, Faraon EJA, Farid T, Farvid MS, Feigin V, Fernandes J, Frostad J, Gebru A, Geleijnse JM, Gona PN, Griswold M, Hailu GB, Hankey GJ, Hassen HY, Havmoeller R, Hay S, Heckbert SR, Irvine CMS, James SL, Jara D, Kasaeian A, Khan AR, Khera S, Khoja AT, Khubchandani J, Kim D, Kolte D, Lal D, Larsson A, Linn S, Lotufo PA, Magdy Abd El Razek H, Mazidi M, Meier T, Mendoza W, Mensah GA, Meretoja A, Mezgebe HB, Mirrakhimov E, Mohammed S, Moran AE, Nguyen G, Nguyen M, Ong KL, Owolabi M, Pletcher M, Pourmalek F, Purcell CA, Qorbani M, Rahman M, Rai RK, Ram U, Reitsma MB, Renzaho AMN, Rios-Blancas MJ, Safiri S, Salomon JA, Sartorius B, Sepanlou SG, Shaikh MA, Silva D, Stranges S, Tabarés-Seisdedos R, Tadele Atnafu N, Thakur JS, Topor-Madry R, Truelsen T, Tuzcu EM, Tyrovolas S, Ukwaja KN, Vasankari T, Vlassov V, Vollset SE, Wakayo T, Weintraub R, Wolfe C, Workicho A, Xu G, Yadgir S, Yano Y, Yip P, Yonemoto N, Younis M, Yu C, Zaidi Z, Zaki MES, Zipkin B, Afshin A, Gakidou E, Lim SS, Mokdad AH, Naghavi M, Vos T, Murray CJL

Abstract
Importance: Cardiovascular disease (CVD) is the leading cause of death in the United States, but regional variation within the United States is large. Comparable and consistent state-level measures of total CVD burden and risk factors have not been produced previously.
Objective: To quantify and describe levels and trends of lost health due to CVD within the United States from 1990 to 2016 as well as risk factors driving these changes.
Design, Setting, and Participants: Using the Global Burden of Disease methodology, cardiovascular disease mortality, nonfatal health outcomes, and associated risk factors were analyzed by age group, sex, and year from 1990 to 2016 for all residents in the United States using standardized approaches for data processing and statistical modeling. Burden of disease was estimated for 10 groupings of CVD, and comparative risk analysis was performed. Data were analyzed from August 2016 to July 2017.
Exposures: Residing in the United States.
Main Outcomes and Measures: Cardiovascular disease disability-adjusted life-years (DALYs).
Results: Between 1990 and 2016, age-standardized CVD DALYs for all states decreased. Several states had large rises in their relative rank ordering for total CVD DALYs among states, including Arkansas, Oklahoma, Alabama, Kentucky, Missouri, Indiana, Kansas, Alaska, and Iowa. The rate of decline varied widely across states, and CVD burden increased for a small number of states in the most recent years. Cardiovascular disease DALYs remained twice as large among men compared with women. Ischemic heart disease was the leading cause of CVD DALYs in all states, but the second most common varied by state. Trends were driven by 12 groups of risk factors, with the largest attributable CVD burden due to dietary risk exposures followed by high systolic blood pressure, high body mass index, high total cholesterol level, high fasting plasma glucose level, tobacco smoking, and low levels of physical activity. Increases in risk-deleted CVD DALY rates between 2006 and 2016 in 16 states suggest additional unmeasured risks beyond these traditional factors.
Conclusions and Relevance: Large disparities in total burden of CVD persist between US states despite marked improvements in CVD burden. Differences in CVD burden are largely attributable to modifiable risk exposures.

PMID: 29641820 [PubMed - as supplied by publisher]

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

To, 12/04/2018 - 02:16
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

Nat Genet. 2018 Apr;50(4):559-571

Authors: Mahajan A, Wessel J, Willems SM, Zhao W, Robertson NR, Chu AY, Gan W, Kitajima H, Taliun D, Rayner NW, Guo X, Lu Y, Li M, Jensen RA, Hu Y, Huo S, Lohman KK, Zhang W, Cook JP, Prins BP, Flannick J, Grarup N, Trubetskoy VV, Kravic J, Kim YJ, Rybin DV, Yaghootkar H, Müller-Nurasyid M, Meidtner K, Li-Gao R, Varga TV, Marten J, Li J, Smith AV, An P, Ligthart S, Gustafsson S, Malerba G, Demirkan A, Tajes JF, Steinthorsdottir V, Wuttke M, Lecoeur C, Preuss M, Bielak LF, Graff M, Highland HM, Justice AE, Liu DJ, Marouli E, Peloso GM, Warren HR, ExomeBP Consortium, MAGIC Consortium, GIANT Consortium, Afaq S, Afzal S, Ahlqvist E, Almgren P, Amin N, Bang LB, Bertoni AG, Bombieri C, Bork-Jensen J, Brandslund I, Brody JA, Burtt NP, Canouil M, Chen YI, Cho YS, Christensen C, Eastwood SV, Eckardt KU, Fischer K, Gambaro G, Giedraitis V, Grove ML, de Haan HG, Hackinger S, Hai Y, Han S, Tybjærg-Hansen A, Hivert MF, Isomaa B, Jäger S, Jørgensen ME, Jørgensen T, Käräjämäki A, Kim BJ, Kim SS, Koistinen HA, Kovacs P, Kriebel J, Kronenberg F, Läll K, Lange LA, Lee JJ, Lehne B, Li H, Lin KH, Linneberg A, Liu CT, Liu J, Loh M, Mägi R, Mamakou V, McKean-Cowdin R, Nadkarni G, Neville M, Nielsen SF, Ntalla I, Peyser PA, Rathmann W, Rice K, Rich SS, Rode L, Rolandsson O, Schönherr S, Selvin E, Small KS, Stančáková A, Surendran P, Taylor KD, Teslovich TM, Thorand B, Thorleifsson G, Tin A, Tönjes A, Varbo A, Witte DR, Wood AR, Yajnik P, Yao J, Yengo L, Young R, Amouyel P, Boeing H, Boerwinkle E, Bottinger EP, Chowdhury R, Collins FS, Dedoussis G, Dehghan A, Deloukas P, Ferrario MM, Ferrières J, Florez JC, Frossard P, Gudnason V, Harris TB, Heckbert SR, Howson JMM, Ingelsson M, Kathiresan S, Kee F, Kuusisto J, Langenberg C, Launer LJ, Lindgren CM, Männistö S, Meitinger T, Melander O, Mohlke KL, Moitry M, Morris AD, Murray AD, de Mutsert R, Orho-Melander M, Owen KR, Perola M, Peters A, Province MA, Rasheed A, Ridker PM, Rivadineira F, Rosendaal FR, Rosengren AH, Salomaa V, Sheu WH, Sladek R, Smith BH, Strauch K, Uitterlinden AG, Varma R, Willer CJ, Blüher M, Butterworth AS, Chambers JC, Chasman DI, Danesh J, van Duijn C, Dupuis J, Franco OH, Franks PW, Froguel P, Grallert H, Groop L, Han BG, Hansen T, Hattersley AT, Hayward C, Ingelsson E, Kardia SLR, Karpe F, Kooner JS, Köttgen A, Kuulasmaa K, Laakso M, Lin X, Lind L, Liu Y, Loos RJF, Marchini J, Metspalu A, Mook-Kanamori D, Nordestgaard BG, Palmer CNA, Pankow JS, Pedersen O, Psaty BM, Rauramaa R, Sattar N, Schulze MB, Soranzo N, Spector TD, Stefansson K, Stumvoll M, Thorsteinsdottir U, Tuomi T, Tuomilehto J, Wareham NJ, Wilson JG, Zeggini E, Scott RA, Barroso I, Frayling TM, Goodarzi MO, Meigs JB, Boehnke M, Saleheen D, Morris AP, Rotter JI, McCarthy MI

Abstract
We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

PMID: 29632382 [PubMed - in process]

Germline alterations in a consecutive series of acute myeloid leukemia.

To, 12/04/2018 - 02:16
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Germline alterations in a consecutive series of acute myeloid leukemia.

Leukemia. 2018 Apr 10;:

Authors: Wartiovaara-Kautto U, Hirvonen EAM, Pitkänen E, Heckman C, Saarela J, Kettunen K, Porkka K, Kilpivaara O

PMID: 29632341 [PubMed - as supplied by publisher]

Doctoral level research and training capacity in the social determinants of health at universities and higher education institutions in India, China, Oman and Vietnam: a survey of needs.

Ke, 11/04/2018 - 02:15
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Doctoral level research and training capacity in the social determinants of health at universities and higher education institutions in India, China, Oman and Vietnam: a survey of needs.

Health Res Policy Syst. 2017 Sep 02;15(1):76

Authors: Ali F, Shet A, Yan W, Al-Maniri A, Atkins S, Lucas H, ARCADE consortium

Abstract
BACKGROUND: Research capacity is scarce in low- and middle-income country (LMIC) settings. Social determinants of health research (SDH) is an area in which research capacity is lacking, particularly in Asian countries. SDH research can support health decision-makers, inform policy and thereby improve the overall health and wellbeing of the population. In order to continue building this capacity, we need to know to what extent training exists and how challenges could be addressed from the perspective of students and staff. This paper aims to describe the challenges involved in training scholars to undertake research on the SDH in four Asian countries - China, India, Oman and Vietnam.
METHODS: In-depth interviews were conducted with research scholars, research supervisors and principal investigators (n = 13) at ARCADE partner institutions, which included eight universities and research institutes. In addition, structured questionnaires (n = 70) were used to collect quantitative data relating to the courses available, teaching and supervisory capacity, and related issues for students being trained in research on SDH. Simple descriptive statistics were calculated from the quantitative data and thematic analysis applied to the qualitative data.
RESULTS: We identified a general lack of training courses focusing on SDH. Added to this, PhD students studying related areas reported inadequate supervision, with limited time allocated to meetings and poor interpersonal communication. Supervisors cited interpersonal communication problems and student lack of skills to perform high quality research as challenges to research training. Further challenges reported included a lack of research funding to include SDH-related topics. Finally, it was suggested that there was a need for institutions to define clear and appropriate standards regarding admission and supervision of students to higher education programs awarding doctoral degrees.
CONCLUSIONS: There are gaps in training for research on the SDH at the surveyed universities and research institutes, which are likely to also be present in other Asian countries and their higher education institutions. Some of the barriers to high quality research and research training can be addressed by improved training for supervisors, clearly defined standards of supervision, finances for student stipends, and increased use of information and communication technology to increase access to teaching materials. Increased opportunities for online learning could be provided.

PMID: 28865472 [PubMed - indexed for MEDLINE]

Case studies investigating genetic heterogeneity between anatomically distinct bone marrow compartments in acute myeloid leukemia.

To, 05/04/2018 - 14:13

Case studies investigating genetic heterogeneity between anatomically distinct bone marrow compartments in acute myeloid leukemia.

Leuk Lymphoma. 2018 Apr 04;:1-4

Authors: Ojamies PN, Kontro M, Edgren H, Ellonen P, Heckman C, Porkka K, Wolf M, Kallioniemi O

PMID: 29616861 [PubMed - as supplied by publisher]

Association analysis identifies 65 new breast cancer risk loci.

Ke, 04/04/2018 - 14:13
Related Articles

Association analysis identifies 65 new breast cancer risk loci.

Nature. 2017 11 02;551(7678):92-94

Authors: Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, Lemaçon A, Soucy P, Glubb D, Rostamianfar A, Bolla MK, Wang Q, Tyrer J, Dicks E, Lee A, Wang Z, Allen J, Keeman R, Eilber U, French JD, Qing Chen X, Fachal L, McCue K, McCart Reed AE, Ghoussaini M, Carroll JS, Jiang X, Finucane H, Adams M, Adank MA, Ahsan H, Aittomäki K, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, Arun B, Auer PL, Bacot F, Barrdahl M, Baynes C, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Børresen-Dale AL, Brand JS, Brauch H, Brennan P, Brenner H, Brinton L, Broberg P, Brock IW, Broeks A, Brooks-Wilson A, Brucker SY, Brüning T, Burwinkel B, Butterbach K, Cai Q, Cai H, Caldés T, Canzian F, Carracedo A, Carter BD, Castelao JE, Chan TL, David Cheng TY, Seng Chia K, Choi JY, Christiansen H, Clarke CL, NBCS Collaborators, Collée M, Conroy DM, Cordina-Duverger E, Cornelissen S, Cox DG, Cox A, Cross SS, Cunningham JM, Czene K, Daly MB, Devilee P, Doheny KF, Dörk T, Dos-Santos-Silva I, Dumont M, Durcan L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Elvira M, Engel C, Eriksson M, Fasching PA, Figueroa J, Flesch-Janys D, Fletcher O, Flyger H, Fritschi L, Gaborieau V, Gabrielson M, Gago-Dominguez M, Gao YT, Gapstur SM, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Glendon G, Goldberg MS, Goldgar DE, González-Neira A, Grenaker Alnæs GI, Grip M, Gronwald J, Grundy A, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hamel N, Hankinson S, Harrington P, Hart SN, Hartikainen JM, Hartman M, Hein A, Heyworth J, Hicks B, Hillemanns P, Ho DN, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Hou MF, Hsiung CN, Huang G, Humphreys K, Ishiguro J, Ito H, Iwasaki M, Iwata H, Jakubowska A, Janni W, John EM, Johnson N, Jones K, Jones M, Jukkola-Vuorinen A, Kaaks R, Kabisch M, Kaczmarek K, Kang D, Kasuga Y, Kerin MJ, Khan S, Khusnutdinova E, Kiiski JI, Kim SW, Knight JA, Kosma VM, Kristensen VN, Krüger U, Kwong A, Lambrechts D, Le Marchand L, Lee E, Lee MH, Lee JW, Neng Lee C, Lejbkowicz F, Li J, Lilyquist J, Lindblom A, Lissowska J, Lo WY, Loibl S, Long J, Lophatananon A, Lubinski J, Luccarini C, Lux MP, Ma ESK, MacInnis RJ, Maishman T, Makalic E, Malone KE, Kostovska IM, Mannermaa A, Manoukian S, Manson JE, Margolin S, Mariapun S, Martinez ME, Matsuo K, Mavroudis D, McKay J, McLean C, Meijers-Heijboer H, Meindl A, Menéndez P, Menon U, Meyer J, Miao H, Miller N, Taib NAM, Muir K, Mulligan AM, Mulot C, Neuhausen SL, Nevanlinna H, Neven P, Nielsen SF, Noh DY, Nordestgaard BG, Norman A, Olopade OI, Olson JE, Olsson H, Olswold C, Orr N, Pankratz VS, Park SK, Park-Simon TW, Lloyd R, Perez JIA, Peterlongo P, Peto J, Phillips KA, Pinchev M, Plaseska-Karanfilska D, Prentice R, Presneau N, Prokofyeva D, Pugh E, Pylkäs K, Rack B, Radice P, Rahman N, Rennert G, Rennert HS, Rhenius V, Romero A, Romm J, Ruddy KJ, Rüdiger T, Rudolph A, Ruebner M, Rutgers EJT, Saloustros E, Sandler DP, Sangrajrang S, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schürmann P, Scott RJ, Scott C, Seal S, Seynaeve C, Shah M, Sharma P, Shen CY, Sheng G, Sherman ME, Shrubsole MJ, Shu XO, Smeets A, Sohn C, Southey MC, Spinelli JJ, Stegmaier C, Stewart-Brown S, Stone J, Stram DO, Surowy H, Swerdlow A, Tamimi R, Taylor JA, Tengström M, Teo SH, Beth Terry M, Tessier DC, Thanasitthichai S, Thöne K, Tollenaar RAEM, Tomlinson I, Tong L, Torres D, Truong T, Tseng CC, Tsugane S, Ulmer HU, Ursin G, Untch M, Vachon C, van Asperen CJ, Van Den Berg D, van den Ouweland AMW, van der Kolk L, van der Luijt RB, Vincent D, Vollenweider J, Waisfisz Q, Wang-Gohrke S, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett W, Winqvist R, Wolk A, Wu AH, Xia L, Yamaji T, Yang XR, Har Yip C, Yoo KY, Yu JC, Zheng W, Zheng Y, Zhu B, Ziogas A, Ziv E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani SR, Antoniou AC, Droit A, Andrulis IL, Amos CI, Couch FJ, Pharoah PDP, Chang-Claude J, Hall P, Hunter DJ, Milne RL, García-Closas M, Schmidt MK, Chanock SJ, Dunning AM, Edwards SL, Bader GD, Chenevix-Trench G, Simard J, Kraft P, Easton DF

Abstract
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

PMID: 29059683 [PubMed - indexed for MEDLINE]

Dual antiplatelet and anticoagulant APAC prevents experimental ischemia-reperfusion-induced acute kidney injury.

Ti, 03/04/2018 - 14:12
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Dual antiplatelet and anticoagulant APAC prevents experimental ischemia-reperfusion-induced acute kidney injury.

Clin Exp Nephrol. 2017 Jun;21(3):436-445

Authors: Tuuminen R, Jouppila A, Salvail D, Laurent CE, Benoit MC, Syrjälä S, Helin H, Lemström K, Lassila R

Abstract
BACKGROUND: Renal ischemia-reperfusion predisposes to acute kidney injury (AKI) and mortality. APAC, mast cell heparin proteoglycan mimetic is a potent dual antiplatelet and anticoagulant inhibiting thrombosis in several vascular models.
METHODS: Clinically relevant (0.06 and 0.13 mg/kg) and high (0.32 and 7.3 mg/kg) heparin doses of APAC and unfractionated heparin (UFH) were administered i.v. in pharmacological studies. Antithrombotic action of APAC and UFH was assessed with platelet aggregation to collagen, activated partial thromboplastin (APTT) and prothrombin (PT) times. Pharmacodynamics of [64Cu]-APAC or -UFH were monitored by PET/CT. Next, APAC and UFH doses (0.06 and 0.13 mg/kg) were i.v. administered 10 min prior to renal ischemia-reperfusion injury (IRI) in rats.
RESULTS: APAC in contrast to UFH inhibited platelet aggregation. During 0.06 and 0.13 mg/kg dose regimens APTT and PT remained at baseline, but at the high APTT prolonged fourfold to sixfold. Overall bio-distribution and clearance of APAC and UFH were similar. After bilateral 30-min renal artery clamping, creatinine, urea nitrogen and neutrophil gelatinase-associated lipocalin concentrations and histopathology indicated faster renal recovery by APAC (0.13 mg/kg). APAC, unlike UFH, prevented expression of innate immune ligand hyaluronan and tubulointerstitial injury marker Kim-1. Moreover, in severe bilateral 1-h renal artery clamping, APAC (0.13 mg/kg) prevented AKI, as demonstrated both by biomarkers and survival. Compatible with kidney protection APAC reduced the circulating levels of vascular destabilizing and pro-inflammatory angiopoietin-2 and syndecan-1. No tissue bleeding ensued.
CONCLUSION: APAC and UFH were similarly eliminated via kidneys and liver. In contrast to UFH, APAC (0.13 mg/kg) was reno-protective in moderate and even severe IRI by attenuating vascular injury and innate immune activation.

PMID: 27405618 [PubMed - indexed for MEDLINE]

Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia...

Su, 01/04/2018 - 14:12
Related Articles

Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT.

Cancer. 2018 Mar 30;:

Authors: Czerw T, Labopin M, Giebel S, Socié G, Volin L, Fegueux N, Masszi T, Blaise D, Chaganti S, Cornelissen JJ, Passweg J, Maertens J, Itälä-Remes M, Wu D, Mohty M, Nagler A

Abstract
BACKGROUND: Mobilized peripheral blood stem cells are currently the predominant source of grafts for allogeneic transplantation (allogeneic peripheral blood stem cell transplantation [allo-PBSCT]), although, in comparison with bone marrow, their use is associated with an increased risk of chronic graft-versus-host disease (cGVHD). Attempts to reduce the incidence of cGVHD include the addition of anti-thymocyte globulin (ATG) to the pretransplant conditioning regimen.
METHODS: The goal of this retrospective study was to analyze the effect of ATG on allo-PBSCT outcomes for adults with Philadelphia-negative acute lymphoblastic leukemia (Ph-neg ALL). The primary endpoint was survival free from relapse, grade 3 to 4 acute graft-versus-host disease (aGVHD), and cGVHD (ie, graft-versus-host disease-free/relapse-free survival [GRFS]). Nine-hundred twenty-four patients who underwent unmanipulated allo-PBSCT in their first complete remission between 2007 and 2016 were included. ATG was used in 97 of the 494 transplants from matched sibling donors (20%) and in 307 of the 430 transplants from human leukocyte antigen-matched (8 of 8 loci) unrelated donors (71%).
RESULTS: The use of ATG was an independent factor for an improved chance of GRFS (hazard ratio [HR], 0.70; P = .0009). Furthermore, it was associated with a reduced risk of both grade 2 to 4 (HR, 0.66; P = .005) and grade 3 to 4 aGVHD (HR, 0.58; P = .03). Similarly, its addition reduced the incidence of both total (HR, 0.45; P < 10-5 ) and extensive cGVHD (HR, 0.30; P < 10-5 ) as well as nonrelapse mortality (HR, 0.58; P = .01). No significant effect was found with respect to leukemia-free or overall survival. However, an increased risk of relapse was noted for those who received ATG (HR, 1.40; P = .04).
CONCLUSIONS: Patients with Ph-neg ALL treated with allo-PBSCT benefit from the use of ATG in terms of improved GRFS. Its use may, therefore, be considered in this setting. Cancer 2018. © 2018 American Cancer Society.

PMID: 29603136 [PubMed - as supplied by publisher]

TEDDI: radiotherapy delivery in deep inspiration for pediatric patients - a NOPHO feasibility study.

To, 29/03/2018 - 14:10
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TEDDI: radiotherapy delivery in deep inspiration for pediatric patients - a NOPHO feasibility study.

Radiat Oncol. 2018 Mar 27;13(1):56

Authors: Lundgaard AY, Hjalgrim LL, Rechner LA, Josipovic M, Joergensen M, Aznar MC, Berthelsen AK, Borgwardt L, Johansen C, Loft A, Safwat A, Vaalavirta L, Specht L, Maraldo MV

Abstract
BACKGROUND: Radiotherapy (RT) delivered in deep inspiration breath-hold (DIBH) is a simple technique, in which changes in patient anatomy can significantly reduce the irradiation of the organs at risk (OARs) surrounding the treatment target. DIBH is routinely used in the treatment of some adult patients to diminish the risk of late effects; however, no formalized studies have addressed the potential benefit of DIBH in children.
METHODS/DESIGN: TEDDI is a multicenter, non-randomized, feasibility study. The study investigates the dosimetric benefit of RT delivered in DIBH compared to free breathing (FB) in pediatric patients. Also, the study aims to establish the compliance to DIBH and to determine the accuracy and reproducibility in a pediatric setting. Pediatric patients (aged 5-17 years) with a tumor in the mediastinum or upper abdomen with the possible need of RT will be included in the study. Written informed consent is obligatory. Prior to any treatment, patients will undergo a DIBH training session followed by a diagnostic PET/CT- or CT-staging scan in both DIBH and FB. If the patient proceeds to RT, a RT planning CT scan will be performed in both DIBH and FB and two separate treatment plans will be calculated. The superior treatment plan, i.e. equal target coverage and lowest overall dose to the OARs, will be chosen for treatment. Patient comfort will be assessed daily by questionnaires and by adherence to the respiratory management procedure.
DISCUSSION: RT in DIBH is expected to diminish irradiation of the OARs surrounding the treatment target and thereby reduce the risk of late effects in childhood cancer survivors.
TRIAL REGISTRATION: The Danish Ethical Committee (H-16035870, approved November 24th 2016, prospectively registered). The Danish Data Protection Agency (2012-58-0004, approved January 1st 2017, prospectively registered). Registered at clinicaltrials.gov ( NCT03315546 , October 20th  2017, retrospectively registered).

PMID: 29587881 [PubMed - in process]

Loss of the hematopoietic stem cell factor GATA2 in the osteogenic lineage impairs trabecularization and mechanical strength of bone.

Ke, 28/03/2018 - 14:09
Related Articles

Loss of the hematopoietic stem cell factor GATA2 in the osteogenic lineage impairs trabecularization and mechanical strength of bone.

Mol Cell Biol. 2018 Mar 26;:

Authors: Tolkachov A, Fischer C, Ambrosi TH, Bothe M, Han CT, Muenzner M, Mathia S, Salminen M, Seifert G, Thiele M, Duda GN, Meijsing SH, Sauer S, Schulz TJ, Schupp M

Abstract
The transcription factor GATA2 is required for expansion and differentiation of hematopoietic stem cells (HSCs). In mesenchymal stem cells (MSCs) GATA2 blocks adipogenesis, but its biological relevance and underlying genomic events are unknown. We report a dual function of GATA2 in bone homeostasis. GATA2 in MSCs binds near genes involved in skeletal system development and co-localizes with motifs for FOX and HOX transcription factors, known regulators of skeletal development. Ectopic GATA2 blocks osteoblastogenesis by interfering with SMAD1/5/8 activation. MSC-specific deletion of GATA2 in mice increases numbers and differentiation capacity of bone-derived precursors, resulting in elevated bone formation. Surprisingly, MSC-specific GATA2 deficiency impairs trabecularization and mechanical strength of bone, involving reduced MSC expression of the osteoclast inhibitor osteoprotegerin and increased osteoclast numbers. Thus, GATA2 affects bone turnover via MSC-autonomous and indirect effects. By regulating bone trabecularization, GATA2 expression in the osteogenic lineage may contribute to the anatomical and cellular microenvironment of the HSC niche required for hematopoiesis.

PMID: 29581184 [PubMed - as supplied by publisher]