Aberrant DNA Methylation Status and mRNA Expression Level of SMG1 Gene in Chronic Myeloid Leukemia: A Case-Control Study

Objective Chronic myeloid leukemia (CML) is a myeloproliferative malignancy with different stages. Aberrant epigeneticmodifications, such as DNA methylation, have been introduced as a signature for diverse cancers which also plays acrucial role in CML pathogenesis and development. Suppressor with morphogenetic effect on genitalia (SMG1) generecently has been brought to the spotlight as a potent tumor suppressor gene that can be suppressed by tumors forfurther progress. The present study aims to investigate SMG1 status in CML patients. Materials and Methods In this case-control study, peripheral blood from 30 patients with different phases of CML [newcase (N)=10, complete molecular remission (CMR)=10, blastic phase (BP)=10] and 10 healthy subjects were collected.Methylation status and expression level of SMG1 gene promoter was assessed by methylation-specific polymerasechain reaction (MSP) and quantitative reverse-transcription PCR, respectively. Results MSP results of SMG1 gene promotor in the new case group were methylated (60% methylated, 30%hemimethylated and 10% unmethylated). All CMR and control group patients were unmethylated in the SMG1 genepromoter. In the BP group, methylated SMG1 promoter was seen (50% of patients had a methylated status and 50%had hemimethylated status). In comparison with the healthy subjects, expression level of SMG1 in the new case groupwas decreased (P<0.01); in the CMR group and BP-CML groups, it was increased (P<0.05). No significant correlationbetween patients’ hematological features and SMG1 methylation was seen. Conclusion Our results demonstrated that aberrant methylation of SMG1 occurred in CML patients and it had asignificant association with SMG1 expression. SMG1 gene promoter showed diverse methylated status and subsequentexpression levels in different phases of CML. These findings suggested possible participation of SMG1 suppression inthe CML pathogenesis

Global systematic review of primary immunodeficiency registries

Introduction During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear. Areas covered Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients. Expert opinion Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.Peer reviewe

Promoter methylation status and expression levels of rassf1a gene in different phases of acute lymphoblastic leukemia (All)

Background: Although the precise pathogenesis of acute lymphoblastic leukemia (ALL) remains unclear, studying gene-regulating mechanisms during ALL pathogeneses may shed light on the underlying mechanisms driving malignant behavior. There is some evidence showing the promoter hypermethylation and silencing of RASSF1A tumor suppressor gene in ALL cells; however, there is a lack of evidence for whether the gene indeed alters during different phases of ALL or in response to therapy. Thus, the current study aimed to clarify this issue using groups of adult ALL patients who have been scarcely investigated regarding expression levels and promoter methylation status. Materials and Methods: In this case/control study, the expression levels and methylation status of the gene promoter was evaluated using quantitative real-time PCR and methylation-specific PCR (MSP), respectively in adults with ALL. The study included peripheral blood of patients with newly diagnosed ALL (n=10), complete remission (CR) (n=10), or relapse (n=10), and 10 control samples from healthy individuals. Results: MSP results revealed an unmethylated status for almost all patients and control samples, except a case with relapsing ALL, which showed a hemimethylated pattern. RASSF1A also showed no difference in terms of gene expression in the patients compared with the control group (p>0.05). Conclusion: The results revealed an up-regulation of RASSF1A tumor suppressor in adult ALL patients experiencing CR, suggesting this to be a marker of therapy response. However, further investigations using more sensitive methylation detecting tools with larger sample sizes may better clarify the involvement of the promoter methylation of RASSF1A in these patients

Comprehensive assessment of respiratory complications in patients with common variable immunodeficiency

[Background] Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by recurrent upper and lower respiratory tract infections and some noninfectious clinical complications.[Objective] To provide a detailed evaluation of respiratory presentations and complications in a cohort of Iranian patients with CVID.[Methods] A retrospective cohort study was conducted on 245 CVID patients who were recorded in the Iranian primary immunodeficiency disorders registry network. Respiratory manifestations were evaluated by reviewing clinical hospital records, immunologic findings, pulmonary function tests (PFT), and high-resolution computed tomography (HRCT) scans.[Results] Most of the patients (n = 208, 85.2%) had experienced at least 1 episode of acute respiratory manifestation, and pneumonia was observed in 31.6 % (n = 77) of cases as a first disease manifestation. During the follow-up, pneumonia, sinusitis, and otitis media were documented in 166 (68.6%), 125 (51.2%), and 103 (42.6%) cases, respectively. Abnormal PFT measurements were documented in 53.8% of patients. Among these patients, 21.5% showed restrictive changes, whereas 18.4% of patients showed an obstructive pattern. Bronchiectasis was the most frequent radiological finding, confirmed in 27.2% of patients. Patients with bronchiectasis were older at the time of immunodeficiency diagnosis (P < .001) and had longer diagnosis delay (P < .001) when compared with patients without bronchiectasis.[Conclusion] This study highlights the importance of monitoring the respiratory tract system even in asymptomatic patients. Pulmonary function tests and CT scans are the most commonly used techniques aiming to identify these patients early, aiming to reduce the rate of long-term respiratory complications.Funding Sources: This research was supported by the Tehran University of Medical Sciences, Tehran, Iran (grant no. 35741)

Evaluation of respiratory complications in patients with X‐linked and autosomal recessive agammaglobulinemia

[Background] Congenital agammaglobulinemia is the first primary immunodeficiency disorder characterized by a defect in B lymphocyte development and subsequently decreased immunoglobulin levels. These patients are prone to suffer from recurrent infections mostly involving the respiratory tract. In this study, we aimed to describe in detail respiratory tract complications as the most prominent clinical feature among agammaglobulinemic patients.[Methods] A total number of 115 patients were included. Demographic, clinical, and genetic data were collected from the patients’ medical records. Among the available patients, pulmonary function tests (PFTs) and/or high‐resolution computed tomography (HRCT) were performed.[Results] Respiratory tract complications (85.2%) especially pneumonia (62.6%) were the most prominent clinical features in our cohort. Among patients with abnormal PFT results (N = 19), a mixed respiratory pattern was observed in 36.8%. HRCT was carried out in 29 patients; Bhalla scoring‐based evaluation of these patients indicated excellent (44.8%), followed by good (34.5%) and mild (20.7%) results. Bronchiectasis was found in 13 patients undergoing HRCT (44.8%). We found significant inverse correlations between the Bhalla score and incidence rate of pneumonia, as well as the presence of bronchiectasis. Patients with abnormal PFT results had statistically significant higher bronchiectasis frequency and lower Bhalla scores compared to those with normal results. Forty‐one patients were deceased, and here, respiratory failure was the most common cause of death (45.5%).[Conclusion] High prevalence of respiratory tract infections among agammaglobulinemic patients and subsequent progression to permanent lung damage highlights the importance of implementing respiratory evaluation as part of routine follow‐up program of agammaglobulinemic patients. Physicians should be aware of this and regularly monitor the respiratory function of these patients to allow for timely diagnosis and treatment initiation aiming to improve patients’ prognosis and quality of life.This work was supported by a grant (37023‐154‐04‐96) from Tehran University of Medical Science