Association of Toll-like receptors polymorphisms with the risk of acute lymphoblastic leukemia in the Brazilian Amazon.

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children in childhood. Single-nucleotide polymorphism (SNPs) in key molecules of the immune system, such as Toll-like receptors (TLRs) and CD14 molecules, are associated with the development of several diseases. However, their role in ALL is unknown. A case-control study was performed with 152 ALL patients and 187 healthy individuals to investigate the role of SNPs in TLRs and the CD14 gene in ALL. In this study, TLR6 C > T rs5743810 [OR: 3.20, 95% CI: 1.11-9.17, p = 0.003) and TLR9 C > T rs187084 (OR: 2.29, 95% CI: 1.23-4.26, p = 0.000) seems to be a risk for development of ALL. In addition, the TLR1 T > G rs5743618 and TLR6 C > T rs5743810 polymorphisms with protection against death (OR: 0.17, 95% IC: 0.04-0.79, p = 0.008; OR: 0.48, 95% IC: 0.24-0.94, p = 0.031, respectively). Our results show that SNPs in TLRs genes may be involved in the pathogenesis of ALL and may influence clinical prognosis; however, further studies are necessary to elucidate the role of TLR1, TLR4, TLR5, TLR6, TLR9 and CD14 polymorphisms in this disease.

Bone Marrow Soluble Immunological Mediators as Clinical Prognosis Biomarkers in B-Cell Acute Lymphoblastic Leukemia Patients Undergoing Induction Therapy.

Different factors are used as predictors of unfavorable clinical outcomes in B-Cell Acute Lymphoblastic Leukemia (B-ALL) patients. However, new prognostic markers are needed in order to allow treatment to be more accurate, providing better results and an improved quality of life. In the present study, we have characterized the profile of bone marrow soluble mediators as possible biomarkers for risk group stratification and minimal residual disease (MRD) detection during induction therapy. The study featured 47 newly-diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients that were categorized into subgroups during induction therapy according to risk stratification at day 15 [Low Risk (LR), Low Risk increasing to High Risk (LR→HR) and High Risk (HR)] and the MRD detection on day 35 (MRD(-) and MRD(+)). Soluble immunological mediators (CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1ß, IL-6, TNF, IFN-γ, IL-17A, IL-4, IL-5, IL-10 and IL-2) were quantified by cytometric bead array and ELISA. Our findings demonstrated that increased levels of CCL5, IFN-γ and IL-2 at baseline appeared as putative candidates of good prognosis in LR and MRD(-) subgroups, while CCL2 was identified as a consistent late biomarker associated with poor prognosis, which was observed on D35 in HR and MRD(+) subgroups. Furthermore, apparently controversial data regarding IL-17A and TNF did not allow the definition of these molecules as either positive or negative biomarkers. These results contribute to the search for novel prognostic indicators, and indicate the potential of bone marrow soluble mediators in prognosis and follow-up of B-ALL patients during induction therapy.

Genetic polymorphisms of inflammasome genes associated with pediatric acute lymphoblastic leukemia and clinical prognosis in the Brazilian Amazon.

The immune system plays an important role in the control of cancer development. To investigate the possible association of inflammasome genes to childhood leukemia we performed a case-control study with 158 patients with acute lymphoblastic leukemia and 192 healthy individuals. The IL1B and IL18 genetic polymorphisms were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and NLRP1, NLRP3 and P2RX7 were genotyped using Real Time quantitative PCR (qPCR). The IL1B C/T rs19644 genotype was associated with the risk of developing ALL (C/C vs. C/T + T/T OR: 2.48 [95% CI: 1.26-4.88, p = 0.006]; C/C vs C/T OR: 2.74 [95% CI: 1.37-5.51, p = 0.003]) and the NLRP1 A/T rs12150220 (OR: 0.37 [95% CI: 0.16-0.87, p = 0.023]) was associated with protection against infectious comorbidities. It was not found association between NLRP3 and P2RX7 polymorphisms and acute lymphoblastic leukemia in our study. Our results suggest that the inflammasome single-variant polymorphisms (SNVs) may play a role in the development and prognostic of childhood leukemia. However, this finds requires further study within a larger population in order to prove it.

Translating Unconventional T Cells and Their Roles in Leukemia Antitumor Immunity.

Recently, cell-mediated immune response in malignant neoplasms has become the focus in immunotherapy against cancer. However, in leukemia, most studies on the cytotoxic potential of T cells have concentrated only on T cells that recognize peptide antigens (Ag) presented by polymorphic molecules of the major histocompatibility complex (MHC). This ignores the great potential of unconventional T cell populations, which include gamma-delta T cells (γδ), natural killer T cells (NKT), and mucosal-associated invariant T cells (MAIT). Collectively, these T cell populations can recognize lipid antigens, specially modified peptides and small molecule metabolites, in addition to having several other advantages, which can provide more effective applications in cancer immunotherapy. In recent years, these cell populations have been associated with a repertoire of anti- or protumor responses and play important roles in the dynamics of solid tumors and hematological malignancies, thus, encouraging the development of new investigations in the area. This review focuses on the current knowledge regarding the role of unconventional T cell populations in the antitumor immune response in leukemia and discusses why further studies on the immunotherapeutic potential of these cells are needed.

Acute lymphoid and myeloid leukemia in a Brazilian Amazon population: Epidemiology and predictors of comorbidity and deaths.

INTRODUCTION: Leukemia is the most common cancer in children and has the highest rates of incidence in industrialized countries, followed by developing countries. This epidemiologic profile can mainly be attributed to the availability of diagnostic resources. In Brazil, leukemia diagnosis is a challenge due to financial viability, lack of hemovigilance services in isolated regions and the vast size of the territory. Its incidence in the state of Amazonas has been increasing since 2010. Therefore, this study aims to describe the epidemiological pattern and spatial distribution of patients with acute lymphoid leukemia and acute myeloid leukemia in Amazonas and identify the predictors of comorbidity and death. MATERIALS AND METHODS: A retrospective cross-sectional study was carried out based on patients' data which was obtained from the database of a referral center for the period of 2005 to 2015. Variables included age, gender, ethnicity, civil status, schooling, income, location of residence, subtype of leukemia, comorbidities, and date of death. The spatial distribution was performed using QGIS v.2.18. Stata software was used for univariable and multivariable logistic regression to evaluate the association between both comorbidities and death for all characteristic groups of ALL and AML. RESULTS: The group that was studied was composed of 577 ALL and 266 AML patients. For both, most patients were male, with a schooling period of 1-4 years, received<1 minimum wage, and lived mostly in Manaus, followed by the municipality of Tefé. There was no association between the development of comorbidities and analyzed variables in patients with ALL. AML patients that were >60 years old and with family history of the disease had the highest risk of developing comorbidities (OR = 5.06, p = 0.038; OR = 2.44, p = 0.041, respectively). Furthermore, patients with ALL and in the 41-50-year age group had a higher risk of death (OR = 31.12; p = 0.001). No association between death and explanatory variables were found in patients with AML. In addition, significant difference was observed in time to death (chi2 = 4,098.32, p = 0.000), with 50% of patients with AML dying within two years after diagnosis, whereas in ALL, this percentual of death only is reached in approximately 5 years. CONCLUSION: Our study describes the data of patients with acute leukemia in Amazonas, a remote region in the north of Brazil. In addition, it highlights the importance of hemovigilance in an Amazon region state, while focusing on peripheral areas which don't have prevention, diagnosis and treatment tools for this disease.

Association of TLR variants with susceptibility to Plasmodium vivax malaria and parasitemia in the Amazon region of Brazil.

BACKGROUND: Plasmodium vivax malaria (Pv-malaria) is still considered a neglected disease despite an alarming number of individuals being infected annually. Malaria pathogenesis occurs with the onset of the vector-parasite-host interaction through the binding of pathogen-associated molecular patterns (PAMPs) and receptors of innate immunity, such as toll-like receptors (TLRs). The triggering of the signaling cascade produces an elevated inflammatory response. Genetic polymorphisms in TLRs are involved in susceptibility or resistance to infection, and the identification of genes involved with Pv-malaria response is important to elucidate the pathogenesis of the disease and may contribute to the formulation of control and elimination tools. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective case-control study was conducted in an intense transmission area of Pv-malaria in the state of Amazonas, Brazil. Genetic polymorphisms (SNPs) in different TLRs, TIRAP, and CD14 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 325 patients infected with P. vivax and 274 healthy individuals without malaria history in the prior 12 months from the same endemic area. Parasite load was determined by qPCR. Simple and multiple logistic/linear regressions were performed to investigate association between the polymorphisms and the occurrence of Pv-malaria and parasitemia. The C/T (TLR5 R392StopCodon) and T/T (TLR9 -1486C/T) genotypes appear to be risk factors for infection by P. vivax (TLR5: C/C vs. C/T [OR: 2.116, 95% CI: 1.054-4.452, p = 0.031]; TLR9: C/C vs. T/T [OR: 1.919, 95% CI: 1.159-3.177, p = 0.010]; respectively). Fever (COEF = 7599.46, 95% CI = 3063.80-12135.12, p = 0.001) and the C/C genotype of TLR9 -1237C/T (COEF = 17006.63, 95% CI = 3472.83-30540.44, p = 0.014) were independently associated with increased parasitemia in patients with Pv-malaria. CONCLUSIONS: Variants of TLRs may predispose individuals to infection by P. vivax. The TLR5 R392StopCodon and TLR9 -1486C/T variants are associated with susceptibility to Pv-malaria. Furthermore, the TLR9 variant -1237C/C correlates with high parasitemia.