Publications by authors named "Mohammad Shahjahani"

47 Publications

Cardiomyopathy in Thalassemia: Quick Review from Cellular Aspects to Diagnosis and Current Treatments.

Lab Med 2020 Mar;51(2):143-150

Child Growth & Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Cardiomyopathic manifestations induced by continuous blood transfusion are the leading cause of death among patients with thalassemia major (TM). Despite introduction of chelation therapy, heart failure after cardiomyopathic manifestations is still a major threat to patients.

Methods: We performed a search of relevant English-language literature, retrieving publications from the PubMed database and the Google Scholar search engine (2005-2018). We used "thalassemia major", "cardiomyopathy", "iron overload", "cardiac magnetic resonance T2" "chelation therapy", and "iron burden" as keywords.

Results: The results of the studies we found suggest that cardiac hepcidin is a major regulator of iron homeostasis in cardiac tissue. Unlike previous assumptions, the heart appears to have a limited regeneration capability, originating from a small population of hypoxic cardiomyocytes.

Conclusions: Oxygen levels determine cardiomyocyte gene-expression patterns. Upregulation of cardiac hepcidin in hypoxia preserves cardiomyocytes from forming out of reactive oxygen species catalyzed by free cellular iron in cardiomyocytes. Using the limited regeneration capacity of cardiac cells and gaining further understanding of the cellular aspects of cardiomyopathic manifestations may help health care professionals to develop new therapeutic strategies.
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http://dx.doi.org/10.1093/labmed/lmz052DOI Listing
March 2020

STAT5: From Pathogenesis Mechanism to Therapeutic Approach in Acute Leukemia.

Lab Med 2020 Jul;51(4):345-351

Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Background: Based on the results of multiple studies, multiple signaling pathways is a major cause of resistence to chemotherapy in leukemia cells. Signal transducer and activator of transcription 5 (STAT5) is among these factors; it plays an essential role in proliferation of leukemic cells.

Methods: We obtained the materials used in our study via PubMed search from 1996 through 2019. The key search terms included "STAT5," "acute leukemia," "leukemogenesis," and "mutation."

Results: On activation, STAT5 not only inhibits apoptosis of leukemic cells via activating the B-cell lymphoma 2 (BCL-2) gene but also inhibits resistance to chemotherapy by enhancing human telomerase reverse transcriptase (hTERT) expression and maintaining telomere length in cells. It has also been shown that a number of mutations in the STAT5 gene and in related genes alter the expression of STAT5.

Conclusion: The identification of STAT5 and the factors activated in its up- or downstream expression, affecting its function, contribute to better treatments such as targeted therapy rather than chemotherapy, improving the quality of life patients.
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http://dx.doi.org/10.1093/labmed/lmz074DOI Listing
July 2020

Complex karyotype in myelodysplastic syndromes: Diagnostic procedure and prognostic susceptibility.

Oncol Rev 2019 Jan 4;13(1):389. Epub 2019 Feb 4.

Thalassemia & Hemoglobinopathy Research center, research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Complex karyotype (CK) is a poor prognosis factor in hematological malignancies. Studies have shown that the presence of CK in myelodysplastic syndrome (MDS) can be associated with MDS progression to acute myeloid leukemia. The goal of this review was to examine the relationship between different types of CK with MDS, as well as its possible role in the deterioration and progression of MDS to leukemia. The content used in this paper has been obtained by a PubMed and Google Scholar search of English language papers (1975-2018) using the terms and . A single independent abnormality can be associated with a good prognosis. However, the coexistence of a series of abnormalities can lead to CK, which is associated with the deterioration of MDS and its progression to leukemia. Therefore, CK may be referred to as a prognostic factor in MDS. The detection of independent cytogenetic disorders that altogether can result in CK could be used as a prognostic model for laboratory and clinical use.
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http://dx.doi.org/10.4081/oncol.2019.389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379782PMC
January 2019

T-bet transcription factor in cardiovascular disease: Attenuation or inflammation factor?

J Cell Physiol 2019 06 7;234(6):7915-7922. Epub 2018 Dec 7.

Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

T-bet is a major transcription factor increasing inflammatory responses in the immune system. Recently, it has been shown that this factor leads to inflammation in cardiovascular disease (CVD). In this study, we examine the dual role of T-bet in inducing and suppressing inflammatory reactions as well as angiogenesis induction due to inflammatory cytokines in CVD. Relevant literature was identified by a Pubmed search (1992-2018) of English-language papers using the terms "T-bet," "Cardiovascular disease," "Immune response," and "Angiogenesis." Although T-bet causes differentiation of Th1 cells and activation of immune cells such as NK and DC, it suppresses inflammatory responses and replaces damaged vessels with new ones by activating regulatory T-cells and stimulating angiogenesis. It can be stated that T-bet acts as double-edged sword. Therefore, the identification of pathways that can increase the function of T-bet in activating Tregs and inducing angiogenesis might be used as a new therapeutic option in future investigations.
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http://dx.doi.org/10.1002/jcp.27935DOI Listing
June 2019

Singe nucleotide polymorphisms in osteosarcoma: Pathogenic effect and prognostic significance.

Exp Mol Pathol 2019 02 7;106:63-77. Epub 2018 Dec 7.

Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Electronic address:

Purpose: Osteosarcoma (OS) is a common malignant bone tumor in children and adolescents. Pathogenesis and prognosis of OS can be associated with several environmental and genetic factors. Single nucleotide polymorphisms (SNPs) are crucial genetic changes that can be involved in clinical and therapeutic outcomes of OS. The aim of this review is to present a synopsis of the role of SNPs in pathogenesis and prognosis of OS tumor cells as well as their potential as therapeutic targets to improve the outcomes of patients.

Method: The content used in this paper has been obtained by an electronic databases search of English language (1998-2018) articles using the terms "Single nucleotide polymorphisms", "Osteosarcoma", "Pathogenesis", "Prognosis", and "Clinical Outcomes".

Discussion: SNPs can affect a number of biological processes such as proliferation, apoptosis, adhesion, invasion, and drug resistance of OS tumor cells, playing a key role in pathogenesis, prognosis, and clinical outcomes after chemotherapy in this disease.

Conclusion: Considering the importance of SNPs in OS pathophysiology, these genetic changes may be used as potential pathogenic and prognostic biomarkers for OS. It is hoped that targeting these changes using new therapeutic approaches leads to the effective treatment of this debilitating tumor. However, better understanding of OS biology and further clinical trials are needed to achieve this goal.
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http://dx.doi.org/10.1016/j.yexmp.2018.12.002DOI Listing
February 2019

Diagnostic Value of HLA Typing in Pathogenesis of Cardiomyopathy.

Cardiovasc Hematol Disord Drug Targets 2019 ;19(2):132-138

Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Development of cardiomyopathy (CM) is dependent upon several factors. However, the reaction of the immune response against myocardial tissue due to microbial and viral infections plays an important role in this disease. Therefore, the purpose of this study is to investigate the relationship between HLAs and their pathogenic mechanisms in the incidence of CM. Relevant literature was identified by a PubMed search (1989-2017) of English-language papers using the terms "Cardiomyopathy", "Human leukocyte antigen or HLA", "immune response", and "polymorphism". If CM patients are afflicted with viral and microbial infections, HLA class II molecules, which are not expressed on myocardial tissue in normal conditions, are mainly expressed on it. As a result, these HLAs present self- antigens and provoke autoimmune responses against myocardial tissue. On the other hand, the occurrence of polymorphism as well as disrupted expression of miRNAs can affect HLA expression, leading to hypertrophy and fibrosis of cardiac muscle. Finally, it is inferred that the expression evaluation of HLAs as well as identification of polymorphisms in their coding genes can be effective diagnostic factors in the detection of people susceptible to CM.
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http://dx.doi.org/10.2174/1871529X19666181205151340DOI Listing
July 2020

Expression of CD markers in JAK2 positive myeloproliferative neoplasms: Prognostic significance.

Oncol Rev 2018 Jul 2;12(2):373. Epub 2018 Oct 2.

Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by the presence of JAK2 mutation. Thrombohemorrhagic as well as autoimmune or inflammatory phenomena are common clinical outcomes of these disorders. Recent studies have shown that abnormality in frequency and function of blood cells manifested by an alteration in CD markers' expression patterns play a key role in these complications. So, there may be a relationship between CD markers' expressions and prognosis of JAK2 positive MPNs. Therefore, in this review, we have focused on these abnormalities from the perspective of changing expressions of CD markers and assessment of the relationship between these changes with prognosis of JAK2 positive MPNs. It can be stated that the abnormal expression of a large number of CD markers can be used as a prognostic biomarker for clinical outcomes including thrombohememorrhagic events, as well as autoimmune and leukemic transformation in JAK2 positive MPNs. Considering the possible role of CD markers' expressions in JAK2 MPNs prognosis, further studies are needed to confirm the relationship between the expression of CD markers with prognosis to be able to find an appropriate therapeutic approach via targeting CD markers.
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http://dx.doi.org/10.4081/oncol.2018.373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199554PMC
July 2018

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

Oncol Rev 2018 Jul 8;12(2):366. Epub 2018 Oct 8.

Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.

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: , , , , and . 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.
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http://dx.doi.org/10.4081/oncol.2018.366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199555PMC
July 2018

Cardiovascular Events: A Challenge in JAK2-positive Myeloproliferative Neoplasms.

Cardiovasc Hematol Disord Drug Targets 2017 ;17(3):161-166

Thalassemia & Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Background: Myeloproliferative neoplasms (MPNs) are chronic blood disorders caused by clonal expansion in one or more myeloid lineages and include essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF) and chronic myeloid leukemia (CML). Cardiovascular events are a main challenge for patients with MPN and can lead to their death.

Objective: JAK2V617F mutation is observed in Philadelphia-negative MPNs such as ET and PV, increasing the risk of cardiovascular complications in these patients. JAK2 mutation can affect cardiac arteries and veins in ET and PV, which results in thrombosis, ischemia and other cardiovascular events. JAK/STAT signaling pathway plays an important role in heart diseases. In this review, we will survey the cardiovascular events in JAK2-positive MPN patients.

Method: Relevant English-language literature were searched and retrieved from PubMed search engine (1995-2017). The following keywords were used: "Cardiovascular Events", "JAK2" and "Myeloproliferative Neoplasms". Forty three articles were selected by using the key words.

Results: JAK2 phosphorylates the signal transducers and activators of transcription (STAT). Various factors like angiotensin II (ANG II) and cardiotrophin-1 (CT-1) can bind their receptors on myocytes and increase the expression of angiotensinogen (Ao) gene by binding of STAT proteins to these factors in myocytes, causing different cardiovascular complications through autocrine mechanisms.

Conclusion: JAK2 mutation is observed in patients with thrombosis, ischemia and other cardiovascular complications having abnormal increase in cell count even without definite clinical diagnosis of MPN. Therefore, identification of this mutation in these patients contributes to definite diagnosis of cardiovascular events. Also, cardiovascular complications in MPN patients can be prevented by targeting the factors involved in JAK/STAT signaling pathway.
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http://dx.doi.org/10.2174/1871529X17666171030122345DOI Listing
March 2019

Sex chromosome changes in leukemia: cytogenetics and molecular aspects.

Hematology 2018 Apr 10;23(3):139-147. Epub 2017 Sep 10.

b Thalassemia & Hemoglobinopathy Research Center, Research Institute of Health , Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran.

Background And Objective: Sex chromosome loss (SCL) can occur in older men as a physiological phenomenon or as an acquired abnormality in leukemia. Loss of chromosome Y and loss of chromosome X are acquired disorders that are mainly observed in patients over 80 years as well as in myeloid and lymphoid malignancies. In this review, we examine the cytogenetic and molecular changes of sex chromosomes in leukemia.

Methods: Relevant English language literature were searched and retrieved from PubMed search engine (1990-2016). The following keywords were used: 'Sex chromosomes', 'Leukemia' and 'Cytogenetics'.

Results: The loss of tumor suppressor genes along with these chromosomal abnormalities in the majority of malignant cells in bone marrow (BM) has raised the question whether this is an age-related phenomenon or has occurred as a result of clonal abnormality. On the other hand, the presence of these chromosomal abnormalities in a number of genetic diseases associated with leukemia leads to progression of malignancy, and their role in peripheral blood stem cell transplantation confirm the finding that these chromosomal abnormalities can play an important role in clonal abnormality.

Conclusion: The presence of these abnormalities can cause genetic instability in BM and result in the development of a malignant clone and progression of the disease. In addition, the evaluation of SCL together with the genes involved in these chromosomes can contribute to predict the disease prognosis as well as monitoring of malignancy.
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http://dx.doi.org/10.1080/10245332.2017.1375063DOI Listing
April 2018

Genetics and Epigenetics of Myelodysplastic Syndromes and Response to Drug Therapy: New Insights.

Oncol Rev 2016 Oct 14;10(2):311. Epub 2016 Dec 14.

Health Research Institute, Thalassemia and Hemoglobinopathy Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz; Colestan Hospital Clinical Research Development Unit. Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

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.
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http://dx.doi.org/10.4081/oncol.2016.311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5178845PMC
October 2016

Bone Marrow Blood Vessels: Normal and Neoplastic Niche.

Oncol Rev 2016 Oct 24;10(2):306. Epub 2016 Nov 24.

Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences , Ahvaz, Iran.

Blood vessels are among the most important factors in the transport of materials such as nutrients and oxygen. This study will review the role of blood vessels in normal bone marrow hematopoiesis as well as pathological conditions like leukemia and metastasis. Relevant literature was identified by a Pubmed search (1992-2016) of English-language papers using the terms , , , and . Given that blood vessels are conduits for the transfer of nutrients, they create a favorable situation for cancer cells and cause their growth and development. On the other hand, blood vessels protect leukemia cells against chemotherapy drugs. Finally, it may be concluded that the vessels are an important factor in the development of malignant diseases.
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http://dx.doi.org/10.4081/oncol.2016.306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5136754PMC
October 2016

Bone marrow niche in immune thrombocytopenia: a focus on megakaryopoiesis.

Ann Hematol 2016 Oct 28;95(11):1765-76. Epub 2016 May 28.

Health Research Institute, Thalassemia and Hemoglobinopathy Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased bleeding tendency and thrombocytopenia. In fact, the precise pathogenesis of this disease is still not clear. Megakaryopoiesis involves complete differentiation of megakaryocyte (MK) progenitors to functional platelets. This complex process occurs in specific bone marrow (BM) niches composed of several hematopoietic and non-hematopoietic cell types, soluble factors, and extracellular matrix proteins. These specialized microenvironments sustain MK maturation and localization to sinusoids as well as platelet release into circulation. However, MKs in ITP patients show impaired maturation and signs of degradation. Intrinsic defects in MKs and their extrinsic environment have been implicated in altered megakaryopoiesis in this disease. In particular, aberrant expression of miRNAs directing MK proliferation, differentiation, and platelet production; defective MK apoptosis; and reduced proliferation and differentiation rate of the MSC compartment observed in these patients may account for BM defects in ITP. Furthermore, insufficient production of thrombopoietin is another likely reason for ITP development. Therefore, identifying the signaling pathways and transcription factors influencing the interaction between MKs and BM niche in ITP patients will contribute to increased platelet production in order to prevent incomplete MK maturation and destruction as well as BM fibrosis and apoptosis in ITP. In this review, we will examine the interaction and role of BM niches in orchestrating megakaryopoiesis in ITP patients and discuss how these factors can be exploited to improve the quality of patient treatment and prognosis.
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http://dx.doi.org/10.1007/s00277-016-2703-1DOI Listing
October 2016

Role of stem cell factor in the placental niche.

Cell Tissue Res 2016 Dec 28;366(3):523-531. Epub 2016 May 28.

Health Research Institute, Thalassemia & Hemoglobinopathy Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Stem cell factor (SCF) is a cytokine found in hematopoietic stem cells (HSCs) and causes proliferation and differentiation of cells by binding to its receptor (c-kit). It is produced in the yolk sac, fetal liver and bone marrow during the development of the fetus and, together with its signaling pathway, plays an important role in the development of these cells. The placenta, an important hematopoiesis site before the entry of cells into the liver, is rich in HSCs, with definitive hematopoiesis in a variety of HSC types and embryonic stem cells. Chorionic-plate-derived mesenchymal stem cells (CP-MSCs) isolated from the placenta show stem cell markers such as CD41 and cause the self-renewal of cells under hypoxic conditions. In contrast, hypoxia can result in apoptosis and autophagy via oxidative stress in stem cells. As a hypoxia-induced factor, SCF causes a balance between cell survival and death by autophagy in CP-MSCs. Stromal cells and MSCs have a crucial function in the development of HSCs in the placenta via SCF expression in the placental vascular niche. Defects in hematopoietic growth factors (such as SCF and its signaling pathways) lead to impaired hematopoiesis, resulting in fetal death and abortion. Therefore, an awareness of the role of the SCF/c-kit pathway in the survival, apoptosis and development of stem cells can significantly contribute to the exploration of stem cell production pathways during the embryonic period and in malignancies and in the further generation of these cells to facilitate therapeutic approaches. In this review, we discuss the role of SCF in the placental niche.
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http://dx.doi.org/10.1007/s00441-016-2429-3DOI Listing
December 2016

The Role of HDACs as Leukemia Therapy Targets using HDI.

Int J Hematol Oncol Stem Cell Res 2015 Oct;9(4):203-14

Health research institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Histone deacetylases (HDACs) are the enzymes causing deacetylation of histone and non-histone substrates. Histone deacetylase inhibitors (HDIs) are a family of drugs eliminating the effect of HDACs in malignant cells via inhibition of HDACs. Due to extensive effects upon gene expression through interference with fusion genes and transcription factors, HDACs cause proliferation and migration of malignant cells, inhibiting apoptosis in these cells via tumor suppressor genes. Over expression evaluation of HDACs in leukemias may be a new approach for diagnosis of leukemia, which can present new targets for leukemia therapy. HDIs inhibit HDACs, increase acetylation in histones, cause up- or down regulation in some genes and result in differentiation, cell cycle arrest and apoptosis induction in malignant cells via cytotoxic effects. Progress in identification of new HDIs capable of tracking several targets in the cell can result in novel achievements in treatment and increase survival in patients. In this review, we examine the role of HDACs as therapeutic targets in various types of leukemia as well as the role of HDIs in inhibition of HDACs for treatment of these malignancies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748691PMC
October 2015

MicroRNA Expression in β-Thalassemia and Sickle Cell Disease: A Role in The Induction of Fetal Hemoglobin.

Cell J 2016 17;17(4):583-92. Epub 2016 Jan 17.

Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Today the regulatory role of microRNAs (miRs) is well characterized in many diverse cel- lular processes. MiR-based regulation is categorized under epigenetic regulatory mecha- nisms. These small non-coding RNAs participate in producing and maturing erythrocytes, expressing hematopoietic factors and regulating expression of globin genes by post-tran- scriptional gene silencing. The changes in expression of miRs (miR-144/-320/-451/-503) in thalassemic/sickle cells compared with normal erythrocytes may cause clinical severity. According to the suppressive effects of certain miRs (miR-15a/-16-1/-23a/-26b/-27a/-451) on a number of transcription factors [myeloblastosis oncogene (MYB), B-cell lymphoma 11A (BCL11A), GATA1, Krüppel-like factor 3 (KLF3) and specificity protein 1 (Sp1)] during β globin gene expression, It has been possible to increasing γ globin gene expression and fetal hemoglobin (HbF) production. Therefore, this strategy can be used as a novel therapy in infusing HbF and improving clinical complications of patients with hemoglobi- nopathies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746408PMC
http://dx.doi.org/10.22074/cellj.2016.3808DOI Listing
February 2016

Rare Cytogenetic Abnormalities and Alteration of microRNAs in Acute Myeloid Leukemia and Response to Therapy.

Oncol Rev 2015 Feb 9;9(1):261. Epub 2015 Mar 9.

Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences , Ahvaz, Iran.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, which is heterogeneous in terms of morphological, cytogenetic and clinical features. Cytogenetic abnormalities, including karyotype aberrations, gene mutations and gene expression abnormalities are the most important diagnostic tools in diagnosis, classification and prognosis in acute myeloid leukemias. Based on World Health Organization (WHO) classification, acute myeloid leukemias can be divided to four groups. Due to the heterogeneous nature of AML and since most therapeutic protocols in AML are based on genetic alterations, gathering further information in the field of rare disorders as well as common cytogenetic abnormalities would be helpful in determining the prognosis and treatment in this group of diseases. Recently, the role of microRNAs (miRNAs) in both normal hematopoiesis and myeloid leukemic cell differentiation in myeloid lineage has been specified. miRNAs can be used instead of genes for AML diagnosis and classification in the future, and can also play a decisive role in the evaluation of relapse as well as response to treatment in the patients. Therefore, their use in clinical trials can affect treatment protocols and play a role in therapeutic strategies for these patients. In this review, we have examined rare cytogenetic abnormalities in different groups of acute myeloid leukemias according to WHO classification, and the role of miRNA expression in classification, diagnosis and response to treatment of these disorders has also been dealt with.
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http://dx.doi.org/10.4081/oncol.2015.261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698590PMC
February 2015

Hepatic metastatic niche: from normal to pre-metastatic and metastatic niche.

Tumour Biol 2016 Feb 11;37(2):1493-503. Epub 2015 Dec 11.

Health research institute, Research Center of Thalassemia &Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Liver is the organ responsible for hematopoiesis during fetal life, which is also a target organ of metastasis for several cancers. In order to recognize the hepatic metastatic changes, obtain a better grasp of cancer prevention, treatment, and inhibition mode of hepatic metastasis progression, we investigate the changes and transformation of normal hepatic niche cells to metastatic niche ones in this review. On the other hand, since metastatic diseases alter the liver function, the changes in a number of cancers that metastasize to the liver have also been reviewed. Relevant English-language literature was searched and retrieved from PubMed (1994-2014) using the following keywords: hepatic stem cell niche, hepatic metastatic niche, chemokine, and microRNAs (miRNAs). Also, over 86 published studies were investigated, and bioinformatics analysis of differentially expressed miRNAs in hepatic cancer and metastasis was performed. Metastasis is developed in several stages with specific changes and mechanisms in each stage. Recognition of these changes would lead to detection of new biomarkers and clinical targets involved in specific stages of liver metastasis. Investigation of the hepatic stem cell niche, development of metastasis in liver tissue, as well as changes in chemokines and miRNAs in metastatic hepatic niche can significantly contribute to faster detection of liver metastasis progression.
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http://dx.doi.org/10.1007/s13277-015-4557-xDOI Listing
February 2016

Wnt/β-catenin signaling in bone marrow niche.

Cell Tissue Res 2016 Feb 16;363(2):321-35. Epub 2015 Oct 16.

Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

The bone marrow (BM) niche is a specific physiological environment for hematopoietic and non-hematopoietic stem cells (HSCs). Several signaling pathways (including Wnt/β-catenin) regulate various aspects of stem cell growth, function and death in the BM niche. In addition, the canonical Wnt pathway is crucial for directing self-renewal and differentiation as important mechanisms in many types of stem cells. We review the role of the Wnt/β-catenin pathway in the BM niche and its importance in stem cells. Relevant literature was identified by a PubMed search (1997-2014) of English-language literature by using the following keywords: BM niche, Wnt/β-catenin signaling, osteoblast, osteoclast and bone disease. The Wnt/β-catenin pathway regulates the stability of the β-catenin proto-oncogene. The stabilized β-catenin then translocates to the nucleus, forming a β-catenin-TCF/LEF complex regulating the transcription of specific target genes. Stem cells require β-catenin to mediate their response to Wnt signaling for maintenance and transition from the pluripotent state during embryogenesis. In adult stem cells, Wnt signaling functions at various hierarchical levels to contribute to the specification of the diverse tissues. Aberrant Wnt/β-catenin signaling and its downstream transcriptional regulators are observed in several malignant stem cells and human cancers. Because Wnt signaling can maintain stem cells and cancer cells, the ability to modulate the Wnt pathway either positively or negatively may be of therapeutic relevance. The controlled activation of Wnt signaling might allow us to enhance stem and progenitor cell activity when regeneration is needed.
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http://dx.doi.org/10.1007/s00441-015-2300-yDOI Listing
February 2016

Bone marrow niche in the myelodysplastic syndromes.

Leuk Res 2015 Oct 14;39(10):1020-7. Epub 2015 Jul 14.

Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

The myelodysplastic syndromes (MDS) are a diverse group of clonal hematopoietic malignancies characterized by ineffective hematopoiesis, progressive bone marrow (BM) failure, cytogenetic and molecular abnormalities, and variable risk of progression to acute myeloid leukemia (AML). The BM microenvironment in MDS plays an important role in the development of this disorder. The BM stromal cells of MDS patients often harbor distinct chromosomal aberrations than the hematopoietic elements, suggesting different genetic origins. Perturbed cytokine secretions from BM stromal cells such as multipotent mesenchymal stem cells (MSCs) and endothelial cells are associated with increased proliferation and survival of malignant hematopoietic cells. Within the MDS BM there are also alterations in stromal cell composition, signaling and angiogenesis between Low- and High-risk MDS patients. Several open lines of investigation into the MDS niche remain, including the timing of stromal defects in context to dysplastic hematopoiesis. Another important, unanswered question is the impact of age on BM stroma function and regulation (or dysregulation) or hematopoietic stem/progenitor cells. With a better understanding of the MDS niche, new therapeutic strategies will emerge.
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http://dx.doi.org/10.1016/j.leukres.2015.06.017DOI Listing
October 2015

Molecular Aspects of Bone Resorption in β-Thalassemia Major.

Cell J 2015 11;17(2):193-200. Epub 2015 Jul 11.

Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

β-thalassemia is the most common single gene disorder worldwide, in which hemoglobin β-chain production is decreased. Today, the life expectancy of thalassemic patients is increased because of a variety of treatment methods; however treatment related complications have also increased. The most common side effect is osteoporosis, which usually occurs in early adulthood as a consequence of increased bone resorption. Increased bone resorption mainly results from factors such as delayed puberty, diabetes mellitus, hypothyroidism, ineffective hematopoiesis as well as hyperplasia of the bone marrow, parathyroid gland dysfunction, toxic effect of iron on osteoblasts, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) deficiency. These factors disrupt the balance between osteoblasts and osteoclasts by interfering with various molecular mechanisms and result in decreased bone density. Given the high prevalence of osteopenia and osteoporosis in thalassemic patients and complexity of their development process, the goal of this review is to evaluate the molecular aspects involved in osteopenia and osteoporosis in thalassemic patients, which may be useful for therapeutic purposes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503833PMC
http://dx.doi.org/10.22074/cellj.2016.3713DOI Listing
July 2015

The bone marrow metastasis niche in retinoblastoma.

Cell Oncol (Dordr) 2015 Aug 11;38(4):253-63. Epub 2015 Jun 11.

Department of Hematology, Allied Medical School, Tehran University of Medical Sciences, Tehran, Iran.

Background: Retinoblastoma (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).

Methods: Here, 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.

Conclusions: The 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.
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http://dx.doi.org/10.1007/s13402-015-0232-xDOI Listing
August 2015

BRAF Mutation in Hairy Cell Leukemia.

Oncol Rev 2014 Sep 23;8(2):253. Epub 2014 Sep 23.

Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences , Ahvaz.

BRAF is a serine/threonine kinase with a regulatory role in the mitogen-activated protein kinase (MAPK) signaling pathway. A mutation in the RAF gene, especially in BRAF protein, leads to an increased stimulation of this cascade, causing uncontrolled cell division and development of malignancy. Several mutations have been observed in the gene coding for this protein in a variety of human malignancies, including hairy cell leukemia (HCL). BRAF V600E is the most common mutation reported in exon15 of BRAF, which is observed in almost all cases of classic HCL, but it is negative in other B-cell malignancies, including the HCL variant. Therefore it can be used as a marker to differentiate between these B-cell disorders. We also discuss the interaction between miRNAs and signaling pathways, including MAPK, in HCL. When this mutation is present, the use of BRAF protein inhibitors may represent an effective treatment. In this review we have evaluated the role of the mutation of the BRAF gene in the pathogenesis and progression of HCL.
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http://dx.doi.org/10.4081/oncol.2014.253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419648PMC
September 2014

Involvement of MicroRNA in T-Cell Differentiation and Malignancy.

Int J Hematol Oncol Stem Cell Res 2015 Jan;9(1):33-49

Department of Pathology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.

MicroRNAs are 19-22 nucleotide RNAs involved in such important processes as development, proliferation, differentiation and apoptosis. Different miRNAs are uniquely expressed in lymphoid T cells, and play a role indevelopment and differentiation of various subtypes by targeting their target genes. Recent studies have shown that aberrant miRNA expression may be involved in T cell leukemogenesis and lymphogenesis, and may function as tumor suppressor (such as miR-451, miR-31, miR-150, and miR-29a) or oncogene (e.g. miR-222, miR-223, miR-17-92, miR-155). MiRNAs can be used as new biomarkers for prognosis and diagnosis or as an index of disease severity in T-cell leukemia and lymphoma. This article presents a review of studies in recent years on the role of miRNAs in T-cell development and their aberrant expression in pathogenesis of T-cell leukemia and lymphoma. Characterizing miRNAs can help recognize their role as new important molecules with prognostic and therapeutic applications.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369232PMC
January 2015

Regulatory effect of chemokines in bone marrow niche.

Cell Tissue Res 2015 Aug 26;361(2):401-10. Epub 2015 Feb 26.

Health research institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Chemokines secreted from different cellular components of bone marrow (BM) play an important role in the formation of the BM niche system. The hematopoietic stem cell (HSC) pool located in specialized anatomical sites within the BM is subjected to a complex network of chemokines, such that the produced chemokines affect the fate of these cells. Expression of different chemokine receptors on leukemic stem cells (LSCs) uncovers the critical role of chemokines in the maintenance, survival and fate of these cells in the leukemic niche. As a pre-metastatic niche rich in a variety of chemokines, the BM niche is turned into a locus of tumor cell development and division. The chemokine receptors expressed on the surface of metastatic cells lead to their metastasis and homing to the BM niche. Knowledge of chemokines and their receptors leads to the production of various therapeutic antagonists at chemokine receptors expressed on leukemic and tumor cells, enabling interference with chemokine function as a therapeutic tool. New findings suggest that miRNAs, with their specific inhibitory function, affect the ability of producing and expressing chemokines and chemokine receptors. This review focuses on the emerging role of chemokines and their receptors in normal and pathologic conditions of the BM niche, and also discusses the new therapeutic methods with this background.
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http://dx.doi.org/10.1007/s00441-015-2129-4DOI Listing
August 2015

Targeting PI3K/AKT/mTOR network for treatment of leukemia.

Cell Mol Life Sci 2015 Jun 25;72(12):2337-47. Epub 2015 Feb 25.

Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.

Objective: Increased activity of PI3K/AKT/mTOR pathway has been observed in a huge number of malignancies. This pathway can function as a prosurvival factor in leukemia stem cells and early committed leukemic precursors and its inhibition is regarded as a therapeutic approach. Accordingly, the aim of this review is to evaluate the PI3K/Akt/mTOR inhibitors used in leukemia models.

Discussion: Inhibition of the PI3K/AKT/mTOR pathway has been reported to have beneficial therapeutic effects in leukemias, both in vitro in leukemia cell lines and in vivo in animal models. Overall, the use of dual PI3K/mTOR inhibitor, dual Akt/RTK inhibitor, Akt inhibitor, selective inhibitor of PI3K, mTOR inhibitor and dual PI3K/PDK1 inhibitor in CML, AML, APL, CLL, B-ALL and T-ALL has a better therapeutic effect than conventional treatments.

Conclusions: Targeting the PI3K/Akt/mTOR pathway may have pro-apoptotic and antiproliferative effects on hematological malignancies. Furthermore, modulation of miRNA can be used as a novel therapeutic approach to regulate the PI3K/Akt/mTOR pathway. However, both aspects require further clinical studies.
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http://dx.doi.org/10.1007/s00018-015-1867-5DOI Listing
June 2015

Immune Thrombocytopenic Purpura in Children and Adults: A Comparative Retrospective Study in IRAN.

Int J Hematol Oncol Stem Cell Res 2014 Jul;8(3):30-6

Health research institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Background: Immune thrombocytopenic purpura (ITP) is an autoimmune disease that can cause bleeding disorders in patients, and presents in acute and chronic forms. The acute form is frequently seen in children, but the chronic form mainly inflicts adults. There are differences and similarities in clinical and laboratory findings of the disease between children and adults. We study these differences and similarities in these two groups of patients with ITP.

Methods: In this study, we retrospectively evaluated the clinical and laboratory data of 323 ITP cases within three years. None of our patients had a history of thrombocytopenia. Patients were classified into two groups of children (3 months to 16 years of age) and adults (≥ 16 years). Data analysis was conducted using SPSS software, and the analysis results were compared between the two age groups.

Results: Overall, the disease prevalence was higher in women than men, but the prevalence of childhood ITP was higher in males than females. The prevalence of initial symptoms including petechiae, purpura and ecchymosis was 60.5% and 61%, respectively in all patients, but severe bleeding rarely occurred in patients (28.8%). 30.5% of patients had a history of infection before developing ITP, and the children had a higher frequency of infection (80.8%). Before treatment, the mean platelet count in adults and children was 33000/μL and 35000/μL, respectively.

Conclusion: Comparison of data in children and adults with ITP indicated similarities and differences in clinical and laboratory findings between the two groups with differences in prevalence, bleeding symptoms, initial platelet count and infection history.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305379PMC
July 2014

Molecular basis of chronic lymphocytic leukemia diagnosis and prognosis.

Cell Oncol (Dordr) 2015 Apr 7;38(2):93-109. Epub 2015 Jan 7.

Department of Hematology and Blood Banking, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Backgrounds: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and is characterized by a clonal accumulation of mature apoptosis-resistant neoplastic cells. It is also a heterogeneous disease with a variable clinical outcome. Here, we present a review of currently known (epi)genetic alterations that are related to the etiology, progression and chemo-refractoriness of CLL. Relevant literature was identified through a PubMed search (1994-2014) of English-language papers using the terms CLL, signaling pathway, cytogenetic abnormality, somatic mutation, epigenetic alteration and micro-RNA.

Results: CLL is characterized by the presence of gross chromosomal abnormalities, epigenetic alterations, micro-RNA expression alterations, immunoglobulin heavy chain gene mutations and other genetic lesions. The expression of unmutated immunoglobulin heavy chain variable region (IGHV) genes, ZAP-70 and CD38 proteins, the occurrence of chromosomal abnormalities such as 17p and 11q deletions and mutations of the NOTCH1, SF3B1 and BIRC3 genes have been associated with a poor prognosis. In addition, mutations in tumor suppressor genes, such as TP53 and ATM, have been associated with refractoriness to conventional chemotherapeutic agents. Micro-RNA expression alterations and aberrant methylation patterns in genes that are specifically deregulated in CLL, including the BCL-2, TCL1 and ZAP-70 genes, have also been encountered and linked to distinct clinical parameters.

Conclusions: Specific chromosomal abnormalities and gene mutations may serve as diagnostic and prognostic indicators for disease progression and survival. The identification of these anomalies by state-of-the-art molecular (cyto)genetic techniques such as fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), single nucleotide polymorphism (SNP) microarray-based genomic profiling and next-generation sequencing (NGS) can be of paramount help for the clinical management of these patients, including optimal treatment design. The efficacy of novel therapeutics should to be tested according to the presence of these molecular lesions in CLL patients.
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http://dx.doi.org/10.1007/s13402-014-0215-3DOI Listing
April 2015

PCR Analysis of IgH and TCR-γ Gene Rearrangements as a Confirmatory Diagnostic Tool for Lymphoproliferative Disorders.

Indian J Hematol Blood Transfus 2015 Mar 4;31(1):38-45. Epub 2014 May 4.

Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

This study investigates PCR analysis of immunoglobulin heavy chain (IgH) and T cell receptor (TCR) gene rearrangements on paraffin-embedded tissue sections and bone marrow aspirates of patients suspected to have lymphoproliferative disorders but with inconclusive diagnosis in histopathological examination. 130 samples of patients with inconclusive immunohistochemistry results were evaluated for clonal rearrangement of IgH and TCR genes. Based on histopathology examination, the patients were divided into three groups: the first group without any definite diagnosis of lymphoproliferative disorders (60 cases, 46.2 %), the second group suspected to have a lymphoproliferative disorder but in favor of benign disorders (19 cases, 14.6 %) and the third group suspect to lymphoproliferative disorders but relatively in favor of malignant disorders (51 cases, 39.2 %). After DNA extraction and quality control, semi-nested PCR was performed using consensus primers for amplification of TCR-γ and CDR-3 regions of IgH genes. PCR products were analyzed after heteroduplex analysis using polyacrylamide gel electrophoresis, and were subject to silver staining. Totally, in over half of the cases (55.4 %), a monoclonal pattern was found in IgH or TCR-γ genes rearrangements. Monoclonal IgH gene rearrangement was detected in 48.1 % of patients, whereas monoclonal TCR-γ gene rearrangement was found in 33.6 % of them, which was not statistically significant (P = 0.008). Only in 32 patients (24.6 %) were the results of TCR-γ and IgH gene rearrangements consistent with respect to the presence (2.3 %) or absence (22.3 %) of monoclonality. Finally, PCR analysis of TCR-γ and IgH gene rearrangements led to definite diagnosis in 105 patients (80.8 %), and only 25 cases (19.2 %) remained inconclusive. Our results emphasize the usefulness of gene rearrangement study in cases without a definite diagnosis in immunohistochemistry studies. Multiple PCR analysis results when combined with patient's clinical course and immunohistochemistry can lead to early diagnosis and subsequent therapy.
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http://dx.doi.org/10.1007/s12288-014-0387-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275529PMC
March 2015

The role of Pax5 in leukemia: diagnosis and prognosis significance.

Med Oncol 2015 Jan 27;32(1):360. Epub 2014 Nov 27.

Department of Hematology and Blood Banking, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.

Pax5 transcription factor, also known as B-cell specific activator protein (BSAP), plays a dual role in the hematopoietic system. Pax5 expression is essential in B-cell precursors for normal differentiation and maturation of B-cells. On the other hand, it inhibits the differentiation and progress toward other lineages. The expression of this factor is involved in several aspects of B-cell differentiation, including commitment, immunoglobulin gene rearrangement, BCR signal transduction and B-cell survival, so that the deletion or inactivating mutations of Pax5 cause cell arrest in Pro-B-cell stage. In recent years, point mutations, deletions and various rearrangements in Pax5 gene have been reported in several types of human cancers. However, no clear relationship has been found between these aberrations and disease prognosis. Specific expression of Pax5 in B-cells can raise it as a marker for the diagnosis and differentiation of B-cell leukemias and lymphomas as well as account for remission or relapse. Extensive studies on Pax5 along with other genes and immunomarkers are necessary for decisive results in this regard.
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http://dx.doi.org/10.1007/s12032-014-0360-6DOI Listing
January 2015