Aziz Sancar Institute of Experimental Medicine

Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data

Fms-like tyrosine kinase 3 (FLT3) and Nucleophosmin1 (NPM1) mutations are the most common molecular variations in acute my-eloid leukemia (AML) and have been associated with prognosis. The frequencies of FLT3, NPM1 mutations in the Algeria population remains unknown due to the lack of data related to this subject. Herein, we aim to investigate the prevalence of these mutations in our population and assess their prognosis impact. Adult AML patients (n= 60) were analyzed for FLT3-internal tandem duplication (ITD), D835Y point mutation and NPM1 exon12 mutations. FLT3-ITD was detected using polymerase chain reaction (PCR), D835Y mutation was detected by restriction fragment length polymorphism (PCR-RFLP) and NPM1 exon12 was detected by Sanger sequencing. The relation between the mutations and the clinical features of the patients was evaluated. FLT3 mutations were present in 11.6% and NPM1 mutations were observed in 15.09% of AML patients. The most frequent NPM1 mutation type was the " type-A mutation " (87.5%). Furthermore, a novel " indel " mutation was also detected in one patient. According to the statistical analysis results, FLT3mut group showed shorter survival time and poor response to the induction therapy, while NPM1 was a predictor of better prognosis in the absence of FLT3 mutations. Our results reveal that FLT3 and NPM1 mutations are less frequent in our population than reported in literature. Patients with isolated NPM1 and FLT3 mutation have different clinical features than those with combined mutations. NPM1 and FLT3 mutations can be used as prognostic factors in AML risk classification.

Background/Aim: This study was designed to provide further evidence for the interactions between hydrogen sulfide (H 2 S) and nitric oxide (NO) in ischemia/reperfusion (I/R) injury. Materials and Methods: Rat hearts were studied with the Langendorff technique using the H 2 S donor sodium hydrosulfide (NaHS, 40 μM) and the cystathionine gamma-lyase (CTH or CSE) inhibitor DL-propargylglycine (PAG, 1 mM). NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 30 mg/kg, 7 days) was administered before the isolation. The hearts were homogenized for biochemical and molecular analysis. Results: NaHS reversed I/R-induced cardiac performance impairment, increased tissue nitric oxide production and decreased tissue markers for cardiac injury, while L-NAME inhibited these effects. The expression of CTH was increased with PAG, which was suppressed by L-NAME. Conclusion: H 2 S and NO increase each other's production suggesting their interaction and cooperation in cardioprotection against I/R injury.

Genome-wide sequencing studies in pediatric cancer cohorts indicate that about 10% of patients have germline mutations within cancer predisposition genes. Within this group, primary immune deficiencies take the priority regarding the vulnerability of the patients to infectious agents and the difficulties of cancer management. On the other hand, early recognition of these diseases may offer specific targeted therapies and hematopoietic stem cell transplantation as an option. Besides therapeutic benefits, early diagnosis will provide genetic counseling for the family members. Within this context, an extended family with multiple consanguineous marriages and affected individuals, who presented with combined immune deficiency (CID) and/or Hodgkin lymphoma phenotype, were examined by exome sequencing. A pathogenic homozygous missense CD70 variation was detected (NM_001252.5:c332C>T) in concordance with CD70 phenotype and familial segregation was confirmed. CD70 variations in patients with CID and malignancy have very rarely been reported. This paper reports extended family with multiple affected members with CID and malignancy carrying a missense CD70 variation, and reviews the rare cases reported in the literature. Primary immune deficiencies appear to be a potential cause for pediatric cancers. Better focusing on these inborn disorders to prevent or make an early diagnosis of malignant transformation and reduce mortalities is important.

Background/Aim: This study was designed to provide further evidence for the interactions between hydrogen sulfide (H 2 S) and nitric oxide (NO) in ischemia/reperfusion (I/R) injury. Materials and Methods: Rat hearts were studied with the Langendorff technique using the H 2 S donor sodium hydrosulfide (NaHS, 40 μM) and the cystathionine gamma-lyase (CTH or CSE) inhibitor DLpropargylglycine (PAG, 1 mM). NO synthase inhibitor L-NGnitroarginine methyl ester (L-NAME, 30 mg/kg, 7 days) was administered before the isolation. The hearts were homogenized for biochemical and molecular analysis. H 2 S and NO increase each other's production suggesting their interaction and cooperation in cardioprotection against I/R injury. Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S), in the order of their discovery, are gasotransmitters, a term that refers to a gaseous transmitter, and was first coined by Wang (1). All are endogenously produced small signaling molecules with low molecular weight (NO, 30 Da; CO, 28 Da; H 2 S, 34 Da). Because they are small gaseous molecules, they reach easily their intracellular targets to activate them, by diffusing freely across the plasma membrane. They play a pivotal roles in the control of many physiological functions, including regulation of cardiovascular, nervous, gastrointestinal, excretory, immune, and reproductive systems (2-5). Of these three gaseous transmitters, H 2 S that was first introduced as a metabolic product in mammals by the American biochemist Vincent Du Vigneaud, has gained much attention in recent years due to its involvement in the above-mentioned physiological functions (2, 6, 7). It is endogenously synthesized in most mammalian tissues from L-cysteine and/or L-homocysteine by cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CTH or CSE), and cysteine aminotransferase together with 3-mercaptopyruvate sulfurtransferase . Heart failure, the major health issue in the world and the leading cause of deaths, is a complicated disease caused by 2507 This article is freely accessible online.

Congenital Erythrocytosis (CE), also called congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. 3 Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and generally results from mutations in the erythropoietin-receptor gene (EPOR). Secondary congenital erythrocytosis arises from conditions which cause tissue hypoxia thus resulting in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (genes HBB, HBA1 and HBA2), decreased production of 2,3-biphosphoglycerate due to mutations in the BPGM gene, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1 and EGLN1). Depending on the affected gene CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive internet-based database focusing on the registration of clinical history, hematological, biochemical and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database (LOVD).

Fms-like tyrosine kinase 3 (FLT3) and Nucleophosmin1 (NPM1) mutations are the most common molecular variations in acute myeloid leukemia (AML) and have been associated with prognosis. The frequencies of FLT3, NPM1 mutations in the Algeria population remains unknown due to the lack of data related to this subject. Herein, we aim to investigate the prevalence of these mutations in our population and assess their prognosis impact. Adult AML patients (n= 60) were analyzed for FLT3-internal tandem duplication (ITD), D835Y point mutation and NPM1 exon12 mutations. FLT3-ITD was detected using polymerase chain reaction (PCR), D835Y mutation was detected by restriction fragment length polymorphism (PCR-RFLP) and NPM1 exon12 was detected by Sanger sequencing. The relation between the mutations and the clinical features of the patients was evaluated. FLT3 mutations were present in 11.6% and NPM1 mutations were observed in 15.09% of AML patients. The most frequent NPM1 mutation type was the "type-A mutation" (87.5%). Furthermore, a novel "indel" mutation was also detected in one patient. According to the statistical analysis results, FLT3mut group showed shorter survival time and poor response to the induction therapy, while NPM1 was a predictor of better prognosis in the absence of FLT3 mutations. Our results reveal that FLT3 and NPM1 mutations are less frequent in our population than reported in literature. Patients with isolated NPM1 and FLT3 mutation have different clinical features than those with combined mutations. NPM1 and FLT3 mutations can be used as prognostic factors in AML risk classification.

Intelectin-1 is an anti-inflammatory adipokine encoded by the Intelectin 1 (ITLN1) gene. Genetic variations in the ITLN1 gene affect the risk of coronary artery disease (CAD) and related CAD risk factors. In this study, we aimed to investigate whether the ITLN1 gene Val109Asp polymorphism has an effect on the severity of CAD and serum lipid levels in both men and women. Methods: A total of 493 subjects who underwent coronary angiography (43.5% women, mean age 63.1±9.5 years) were grouped as individuals with critical CAD (≥70% stenosis, n=202), non-critical CAD (31%-69% stenosis, n=90), and non-CAD (control group) (1%-30% stenosis, n=201). Genotyping was performed using LightSNiP assay in Real-Time PCR. Results: The frequency of the Val allele was significantly different among all the patients with critical CAD (n=41) and non-CAD control (n=51) groups in women (p=0.033) but not in men (n=77 and n=38). Women with the Val allele had a 1.69-fold increased risk for critical CAD (p=0.033). In addition, the presence of Val allele was associated with higher coronary stenosis after adjustment for several confounders only in women with critical CAD (p=0.025). Furthermore, carriers of the Val allele exhibited an increased low-density lipoprotein cholesterol (LDL-C) in men with critical CAD than in those with non-CAD (p<0.05). Conclusion: These results suggest that the Val allele of the ITLN1 Val109Asp polymorphism is associated with critical CAD and high LDL-C levels in our study population. Further studies are required to elucidate the effect of Val109Asp polymorphism on CAD pathogenesis.

Objective: Coronary artery disease (CAD) is an important public health problem worldwide. Therefore, it is important to identify the molecular mechanisms and the candidate gene polymorphisms involved in the development of CAD. In this study, we focused on 2 polymorphisms of the atherosclerosis-related genes, ESR1 and CYP19A1. Methods: Unselected 339 individuals who underwent coronary angiography were divided into 2 groups: those with normal coronary arteries (≤30% stenosis) and those with critical disease (≥50% stenosis). Individuals were genotyped for CYP19A1 rs10046 C/T and ESR1 rs2175898 A/G polymorphisms using hybridization probes in real-time PCR. In addition, Gensini and SYNTAX scores were assessed. Results: ESR1 polymorphism was significantly associated with CAD in men (p=0.036) via G allele carriage. Multiple logistic regression analyses showed that ESR1 rare allele carriage was associated with CAD presence (Odds ratio=2.12, 95% confidence interval 1.01-4.1, p=0.025), adjusted for age, HDL-C, LDL-C and smoking status in the male group. CYP19A1 rs10046 T allele carriers had a 2.84-fold increased risk for complex CAD in multiple logistic regression analysis (p=0.016). Furthermore, the univariate analysis of variance indicated that T allele carriage of rs10046 polymorphism was associated with increased SYNTAX and Gensini scores (p<0.05). Female patients who were ESR1 G allele carriers with CAD had higher adiponectin levels (p=0.005), whereas HbA1c levels were associated with T allele of CYP19A1 in the CAD group (p=0.004) and male CAD group (p=0.018). Conclusion: The CYP19A1 and ESR1 polymorphisms were associated with the presence and severity of CAD. These gene polymorphisms warrant further studies for the elucidation of their contribution to CAD development.