Abbas Khosravi

The bone marrow metastasis niche in retinoblastoma

BackgroundRetinoblastoma (Rb) is a progressive cancer which mainly occurs in children, and which is caused by different genetic or epigenetic alterations that lead to inactivation of both alleles of the RB1 gene. Hereditary and non-hereditary forms of Rb do exist, and the hereditary form is associated with an increased risk of secondary malignancies. Metastasis to distant organs is a critical feature of many tumors, and may be caused by various molecular alterations at different stages. Recognition of these alterations and, thus, insight into the processes underlying the development of metastases may result in novel preventive as well as effective targeted treatment options. Rb is associated with metastases to various organs and tissues, including the bone marrow (BM).MethodsHere, we provide an overview of mutations and other molecular changes known to be involved in Rb development and metastasis to the BM. This overview is based on a literature search ranging from 1990 to 2015.ConclusionsThe various BM metastasis-related molecular changes identified to date may be instrumental for a better diagnosis, prognosis and classification of Rb patients, as well as for the development of novel comprehensive (targeted) therapies.

Genetics and epigenetics of myelodysplastic syndromes and response to drug therapy: new insights

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms ocurring mostly in the elderly. The clinical outcome of MDS patients is still poor despite progress in treatment approaches. About 90% of patients harbor at least one somatic mutation. This review aimed to assess the potential of molecular abnormalities in understanding pathogenesis, prognosis, diagnosis and in guiding choice of proper therapy in MDS patients. Papers related to this topic from 2000 to 2016 in PubMed and Scopus databases were searched and studied. The most common molecular abnormalities were TET2, ASXL1 as well as molecules involved in spliceosome machinery (U2AF1, SRSF2 and SF3B1). Patients with defects in TET2 molecule show better response to treatment with azacitidine. IDH and DNMT3A mutations are associated with a good response to decitabine therapy. In addition, patients with del5q subtype harboring TP53 mutation do not show a good response to lenalidomide therapy. In general, the results of this study show that molecular abnormalities can be associated with the occurrence of a specific morphological phenotype in patients. Therefore, considering the morphology of patients, different gene profiling methods can be selected to choice the most appropriate therapeutic measure in these patients in addition to faster and more cost-effective diagnosis of molecular abnormalities.

Evaluation of α-Globin Gene Mutations Among Different Ethnic Groups in Khuzestan Province, Southwest Iran

Abstract α-Thalassemia (α-thal) is one of the most common inherited hemoglobin (Hb) disorders in the world. In addition to large deletions, over 50 different α-thal point mutations were detected around the world, thus, patients showed different phenotypes with regard to genotype. This study evaluated the genetic frequency of α-thal in Khuzestan Province, Southwest Iran, to help implement premarital and prenatal screening programs. The study was conducted on couples proposing to get married and parents who were referred to the genetic center of Shafa Hospital, Ahvaz, Iran, for prenatal diagnosis (PND) in 2012. Genomic DNA was purified by the salting-out method and tested using multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system-PCR (ARMS-PCR), reverse hybridization test strips and DNA sequencing. Overall, 11 mutations were found on the α-globin genes. Based on gene frequency, the most common mutant allele was –α3.7 (rightward) (71.3%) followed by the two gene deletion – –MED (9.7%). Other common mutations were αcodon 19α (GCG>GC–, α2) (8.4%), the polyadenylation (polyA1) site αpolyA1α (AATAAA>AATAAG) (2.8%), and α–5 ntα (–TGAGG) (2.0%). In addition, an extremely rare mutation at αcodon 21α [Hb Fontainebleau, HBA2: c.64G > C (or HBA1)] was also found. The results of this study are critical for correct diagnosis of α-thal carriers, premarriage counseling and PND. This study suggests that the distribution of mutations on the α-globin genes differs among the ethnic groups in Khuzestan Province as well as in other provinces.

Cytogenetic and molecular basis of BCR-ABL myelodysplastic syndrome: diagnosis and prognostic approach

Myelodysplastic syndromes (MDS) include a heterogeneous group of blood disorders generally afflicting older people. Several genetic factors have been reported from these patients that have an important role in the diagnosis, prognosis, and treatment of this disease. BCR-ABL1 is a genetic factor that has occasionally been reported in some studies. This review attempts to characterize MDS patients reported to harbor this fusion and to assess the diagnostic, therapeutic, and prognostic potential of BCR-ABL1 fusionin MDS patients. This review showed that BCR-ABL fusion has been reported in 22 MDS patients whose condition generally transformed to acute myeloblastic leukemia and was not responsive to conventional therapies. However, these patients showed a good response to treatment with tyrosine kinase inhibitors. Therefore, even though incidence of BCR-ABL fusion appears to be low in MDS patients, its detection is essential in assessing disease prognosis and choosing appropriate treatment.

Molecular and cellular aspects of extramedullary manifestations of acute myeloid leukemia

Molecular and cellular aspects of extramedullary manifestations of acute myeloid leukemia Javad Mohammadiasl1, Abbas Khosravi2, Mohammad Shahjahani2, Shirin Azizidoost2, Najmaldin Saki2 1Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran. 2Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran. Correspondence to: Dr. Najmaldin Saki, Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran. E-mail: najmaldinsaki@gmail.com The myeloid extramedullary tumor is a solid tumor formed by infiltration of immature myeloid cells in various tissues of the body. This tumor is also identified as chloroma or myeloid sarcoma (MS). MS is a manifestation of acute myeloid leukemia (AML) occurring at presentation or during treatment or relapse. MS is associated with multiple chromosomal abnormalities and molecular mutations since patients with these disorders bear a high potential for MS manifestation. There is a high incidence of extramedullary infiltration (EMI) in AML. AML patients with EMI have a worse prognosis than patients without it. Hematopoietic stem cells and leukemic stem cells reside in a special bone marrow microenvironment called niche, which is essential for their normal functions. Cancers are exploited dysfunctional cell-cell and matrix-cell interactions, which convert a normal niche into a neoplastic niche. This study summarizes the current knowledge on the molecular and cellular characteristics of AML with EMI and extramedullary niches in AML patients.

The impact of Mir-9 regulation in normal and malignant hematopoiesis

MicroRNA-9 (MiR-9) dysregulation has been observed in various cancers. Recently, MiR-9 is considered to have a part in hematopoiesis and hematologic malignancies. However, its importance in blood neoplasms is not yet well defined. Thus, this study was conducted in order to assess the significance of MiR-9 role in the development of hematologic neoplasia, prognosis, and treatment approaches. We have shown that a large number of MiR-9 targets (such as FOXOs, SIRT1, CCND1, ID2, CCNG1, Ets, and NFkB) play essential roles in leukemogenesis and that it is overexpressed in different leukemias. Our findings indicated MiR-9 downregulation in a majority of leukemias. However, its overexpression was reported in patients with dysregulated MiR-9 controlling factors (such as MLLr). Additionally, prognostic value of MiR-9 has been reported in some types of leukemia. This study generally emphasizes on the critical role of MiR-9 in hematologic malignancies as a prognostic factor and a therapeutic target.

Dual inhibition of PI3K/mTOR signaling in chemoresistant AML primary cells

A main cause of treatment failure for AML patients is resistance to chemotherapy. Survival of AML cells may depend on mechanisms that elude conventional drugs action and/or on the presence of leukemia initiating cells at diagnosis, and their persistence after therapy. MDR1 gene is an ATP-dependent drug efflux pump known to be a risk factor for the emergence of resistance, when combined to unstable cytogenetic profile of AML patients. In the present study, we analyzed the sensitivity to conventional chemotherapeutic drugs of 26 samples of primary blasts collected from AML patients at diagnosis. Detection of cell viability and apoptosis allowed to identify two group of samples, one resistant and one sensitive to in vitro treatment. The cells were then analyzed for the presence and the activity of P-glycoprotein. A comparative analysis showed that resistant samples exhibited a high level of MDR1 mRNA as well as of P-glycoprotein content and activity. Moreover, they also displayed high PI3K signaling. Therefore, we checked whether the association with signaling inhibitors might resensitize resistant samples to chemo-drugs. The combination showed a very potent cytotoxic effect, possibly through down modulation of MDR1, which was maintained also when primary blasts were co-cultured with human stromal cells. Remarkably, dual PI3K/mTOR inactivation was cytotoxic also to leukemia initiating cells. All together, our findings indicate that signaling activation profiling associated to gene expression can be very useful to stratify patients and improve therapy.

Vitamin D and its receptor polymorphisms: New possible prognostic biomarkers in leukemias

Several factors such as chromosomal translocations, gene mutations, and polymorphisms are involved in the pathogenesis of leukemia/lymphoma. Recently, the role of vitamin D (VD) and vitamin D receptor (VDR) polymorphisms in hematologic malignancies has been considered. In this review, we examine the possible role of VD levels, as well as VDR polymorphisms as prognostic biomarkers in leukemia/lymphoma. Relevant English language literature were searched and retrieved from Google Scholar search engine (1985-2017). The following keywords were used: vitamin D, vitamin D receptor, leukemia, lymphoma, and polymorphism. Increased serum levels of VD in patients with leukemia are associated with a better prognosis. However, low VD levels are associated with a poor prognosis, and VDR polymorphisms in various leukemias can have prognostic value. VD biomarker can be regarded as a potential prognostic factor for a number of leukemias, including acute myeloblastic leukemia (AML), chronic lymphoblastic leukemia (CLL), and diffuse large B-cell lymphoma (DLBCL). There is a significant relationship between different polymorphisms of VDR (including Taq I and Fok I) with several leukemia types such as ALL and AML, which may have prognostic value.

Significance of genetic polymorphisms in hematological malignancies: implications of risk factors for prognosis and relapse

SummaryBackgroundLeukemia is one of the most important hematological malignancies. Despite progress in leukemia therapy, recurrence is still one of the main reasons for treatment failure. Recently, gene polymorphisms have been the focus of attention as important factors in the recurrence of leukemia.MethodsRelevant literature was identified by an electronic database search (1996–2018) of English-language literature using the terms “polymorphism”, “leukemia”, “prognosis”, “lymphoma”, and “relapse.”ResultsPolymorphisms of genes involved in cell cycle, apoptosis, immune system, and drug metabolism enzymes have been associated with progression of hematological malignancies. These genetic changes can be associated with relapse and unfavorable clinical outcomes through potential impact on leukemic cells survival.ConclusionConsidering the fact that gene polymorphisms could significantly affect pathophysiology of hematological malignancies, these genetic changes may be considered as potential prognostic biomarkers and therapeutic agents in these disorders.

Hepatitis C virus prevalence among patients with thalassemia and inherited bleeding disorders in Iran: a systematic review and meta-analysis

Among blood products transmitted viral infections, hepatitis C as the most important cause of post-transfusion complication corresponding to the 90% of post transfusion hepatitis.1 Patients who require multi blood transfusion like patients with hereditary bleeding disorders and major thalassemia are noticeably at high risk of transfusion-transmitted infections.2,3 Hepatitis C virus is a single-stranded RNA virus which is the main cause of non-A non-B hepatitis recognized in 1989.4 HCV infection affected about 2-3% of the population and is a global health problem.5 Clinically, it presents in two acute and chronic forms. Acute form is usually asymptomatic and rarely accompanies life-threatening conditions. Also, fifteen to forty-five percent of cases are treated within 6 months without any treatment. On the other hand 60% to 80% of subjects develop chronic form of disease which is a leading cause of liver cirrhosis within 20 years.6 HCV as the main cause of chronic liver disease is responsible for the most hepatocellular carcinomas and requires intensive care. Hereditary bleeding diseases (i.e. Hemophilia, Von Willebrand disease, clotting factors deficiency and etc.) are a group of conditions that result when the coagulation system doesn’t function properly and patients experience extended bleeding after injury or even spontaneously. Thalassemia is a group of inherited disorders of the globin chain synthesis in which hemoglobin is reduced or absent. Thalassemia is classified based on the type of affected chain (alpha(α) or beta(β) thalassemia & ...). Major β-thalassemia reveals with a severe anemia about 6 months after birth and in the absence of treatment causes developmental disorder and skeletal malformation and ultimately reduces the patient’s life. Therefore, regular blood transfusions are deemed necessary in these patients.7