Validation and functional characterization of GWAS-identified variants for chronic lymphocytic leukemia: a CRuCIAL study

This work was partially supported by the European Union's Horizon 2020 research and innovation program (grant No 856620); grants from the Instituto de Salud Carlos III (Madrid, Spain; PI17/02256 and PI20/01845); Consejeria de Economia, Conocimiento, Empresas y Universidad (Granada, Spain; A-CTS-448-UGR18); Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades (Sevilla, Spain; PY20/01282); Generalitat de Catalunya (17SGR437); Gilead Sciences Fellowship (GLD17/00282); the "Xarxa de Bancs de tumors" sponsored by Pla Director d'Oncologia de Catalunya (XBTC); the Associazione Italiana per la Ricerca sul Cancro and Fondazione Cariplo (TRIDEO 16923 and AIRC IG21436); the Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE; and the Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), action Genrisk. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.In conclusion, this study confirmed the association of 31 GWASidentified SNPs with CLL risk and shed some light on the function of some of these biomarkers in the modulation of TReg, B, and T cell differentiation and proliferation, blood concentrations of B cell-related proteins, cell survival, and the expression of immuneand non-immune-related loci. Though outside the scope of the current study, it is important to mention that additional functional studies using blood samples from CLL patients are still required to validate our findings and to decipher the exact biological mechanisms behind the observed associations. A potential limitation of this work was the relatively small population size of the CRuCIAL cohort that hampered the validation of the SNPs showing modest associations.European Union's Horizon 2020 research and innovation program 856620Instituto de Salud Carlos III PI17/02256 PI20/01845Consejeria de Economia, Conocimiento, Empresas y Universidad (Granada, Spain) A-CTS-448-UGR18 Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades (Sevilla, Spain) PY20/01282Generalitat de CatalunyaGeneral Electric 17SGR437Gilead Sciences GLD17/00282"Xarxa de Bancs de tumors" - Pla Director d'Oncologia de Catalunya (XBTC)Fondazione AIRC per la ricerca sul cancro Fondazione Cariplo TRIDEO 16923 AIRC IG21436Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MOREConsortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), action Genris

Autophagy in Hematological Malignancies

Autophagy is a highly conserved metabolic pathway via which unwanted intracellular materials, such as unfolded proteins or damaged organelles, are digested. It is activated in response to conditions of oxidative stress or starvation, and is essential for the maintenance of cellular homeostasis and other vital functions, such as differentiation, cell death, and the cell cycle. Therefore, autophagy plays an important role in the initiation and progression of tumors, including hematological malignancies, where damaged autophagy during hematopoiesis can cause malignant transformation and increase cell proliferation. Over the last decade, the importance of autophagy in response to standard pharmacological treatment of hematological tumors has been observed, revealing completely opposite roles depending on the tumor type and stage. Thus, autophagy can promote tumor survival by attenuating the cellular damage caused by drugs and/or stabilizing oncogenic proteins, but can also have an antitumoral effect due to autophagic cell death. Therefore, autophagy-based strategies must depend on the context to create specific and safe combination therapies that could contribute to improved clinical outcomes. In this review, we describe the process of autophagy and its role on hematopoiesis, and we highlight recent research investigating its role as a potential therapeutic target in hematological malignancies. The findings suggest that genetic variants within autophagy-related genes modulate the risk of developing hemopathies, as well as patient survival

Polymorphisms within the TNFSF4 and MAPKAPK2 Loci influence the risk of developing invasive aspergillosis: A two-stage case control study in the context of the aspBIOmics consortium

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.This study was supported by grants PI20/01845, PI12/02688, and ISCIII-FEDER PI17/02276 from Fondo de Investigaciones Sanitarias (Madrid, Spain), PIM2010EPA-00756 from the ERA-NET PathoGenoMics (0315900A), the Collaborative Research Center/Transregio 124 FungiNet, the Fundacao para a Ciencia e Tecnologia (FCT) (PTDC/SAU-SER/29635/2017, PTDC/MED-GEN/28778/2017, CEECIND/03628/2017, and CEECIND/04058/2018), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 847507, and the "la Caixa" Foundation (ID 100010434) and FCT under the agreement LCF/PR/HP17/52190003)

Genetic polymorphisms associated with telomere length and risk of developing myeloproliferative neoplasms

D.C., F.C., and M.G. conceived and designed the study. A.M. and M.G. performed labwork. A.M., F.C., D.C., and M.G. drafted the manuscript. A.M., F.C., D.C., and M.G. performed data quality control and statistical analyses. All other authors provided samples and data. All authors critically read, commented, and approved the manuscript.Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the “teloscore” in 480 MPN patients and 909 healthy controls in a European multi-center case–control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24–2.68, P = 2.21 × 10−3, comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (ORallelic= 1.43; 95% CI 1.15–1.77; P = 1.35 × 10−3). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN developmen

Genetic polymorphisms associated with telomere length and risk of developing myeloproliferative neoplasms

Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the "teloscore" in 480 MPN patients and 909 healthy controls in a European multi-center case-control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24-2.68, P = 2.21 × 10-3, comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (ORallelic = 1.43; 95% CI 1.15-1.77; P = 1.35 × 10-3). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN development.This work was partially supported by intramural funds of Univerity of Pisa and DKFZ, and by the Italian Ministry of Health grants to the Division of Gastroenterology, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo (F.G.), Italy and by the “5 × 1000” voluntary contribution.Open access funding provided by Projekt DEA.Ye

Autophagy in Hematological Malignancies.

Autophagy is a highly conserved metabolic pathway via which unwanted intracellular materials, such as unfolded proteins or damaged organelles, are digested. It is activated in response to conditions of oxidative stress or starvation, and is essential for the maintenance of cellular homeostasis and other vital functions, such as differentiation, cell death, and the cell cycle. Therefore, autophagy plays an important role in the initiation and progression of tumors, including hematological malignancies, where damaged autophagy during hematopoiesis can cause malignant transformation and increase cell proliferation. Over the last decade, the importance of autophagy in response to standard pharmacological treatment of hematological tumors has been observed, revealing completely opposite roles depending on the tumor type and stage. Thus, autophagy can promote tumor survival by attenuating the cellular damage caused by drugs and/or stabilizing oncogenic proteins, but can also have an antitumoral effect due to autophagic cell death. Therefore, autophagy-based strategies must depend on the context to create specific and safe combination therapies that could contribute to improved clinical outcomes. In this review, we describe the process of autophagy and its role on hematopoiesis, and we highlight recent research investigating its role as a potential therapeutic target in hematological malignancies. The findings suggest that genetic variants within autophagy-related genes modulate the risk of developing hemopathies, as well as patient survival

Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower-risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia

Grupo Andaluz SMD.In this prospective trial, the efficacy of azacitidine in lower-risk myelodysplastic syndromes (LR-SMD) lacking del(5q) was compared to best supportive care (BSC) at 1:1. The primary endpoint was the achievement of erythroid hematologic improvement (HI-E) after nine cycles. Thirty-six patients received at least ≥1 cycle. HI-E was confirmed 44.4% randomized to Aza and in 5.5% of patients receiving BSC (p <.01). After entry in Aza extension period, transfusion independence was achieved in all Aza responders with a median duration of 50 weeks (range: 17–231). No significant differences were observed in secondary endpoints. Importantly, variant allele frequency (VAF) of some mutated genes (RET, SF3B1, ASXL1) decreased after 9 months of treatment in Aza-responder patients. In conclusion, LR-MDS patients lacking del5q and resistant to ESAs, who receive 5 days Aza, achieve TI in a substantial proportion of cases and results in modifications in mutational landscape.Peer Reviewe

Validation and functional characterization of GWAS-identified variants for chronic lymphocytic leukemia: a CRuCIAL study.

Altres ajuts: Junta de Andalucia Consejería de Transformación Económica, Industria, Conocimiento y Universidades (PY20/01282