Autophagy in Hematological Malignancies: Molecular Aspects in Leukemia and Lymphoma.

The organization of the hematopoietic system is dependent on hematopoietic stem cells (HSCs) that are capable of self-renewal and multilineage differentiation to produce different blood cell lines. Autophagy has a central role in energy production and metabolism of the cells during starvation, cellular stress adaption, and removing mechanisms for aged or damaged organelles. The role and importance of autophagy pathways are becoming increasingly recognized in the literature because these pathways can be useful in organizing intracellular circulation, molecular complexes, and organelles to meet the needs of various hematopoietic cells. There is supporting evidence in the literature that autophagy plays an emerging role in the regulation of normal cells and that it also has important features in malignant hematopoiesis. Understanding the molecular details of the autophagy pathway can provide novel methods for more effective treatment of patients with leukemia. Overall, our review will emphasize the role of autophagy and its different aspects in hematological malignant neoplasms.

The Dual Role of ROS in Hematological Malignancies: Stem Cell Protection and Cancer Cell Metastasis.

BACKGROUND AND OBJECTIVE: Reactive oxygen species (ROS) play crucial role in hematopoiesis, regulation of differentiation, self-renewal, and the balance between quiescence and proliferation of hematopoietic stem cells (HSCs). The HSCs are a small population of undifferentiated cells that reside in the bone marrow (BM) and can undergo self-renewal by giving rise to mature cells. METHODS: Relevant literature was identified through a PubMed search (2000-2019) of English-language papers using the following terms: reactive oxygen species, hematopoietic stem cell, leukemic stem cell, leukemia and chemotherapy. RESULTS: HSCs are very sensitive to high levels of ROS and increased production of ROS have been attributed to HSC aging. HSC aging induced by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration. In addition, the elevated ROS levels might even trigger differentiation of Leukemic stem cells (LSCs) and ROS may be involved in the initiation and progression of hematological malignancies, such as leukemia. CONCLUSION: Targeting genes involved in ROS in LSCs and HSCs are increasingly being used as a critical target for therapeutic interventions. Appropriate concentration of ROS may be an optimal therapeutic target for treatment of leukemia during chemotherapy, but still more studies are required to better understanding of the of ROS role in blood disorders.

Clonal hematopoiesis: Genes and underlying mechanisms in cardiovascular disease development.

The clonal hematopoiesis when occurring without hematologic abnormalities is defined as clonal hematopoiesis of indeterminate potential (CHIP). Aging causes accumulation of somatic mutations, and hematopoietic stem cells (HSCs) can develop clonal expansion of different lineages by these mutations. CHIP has a correlation with cancer and cardiovascular disease (CVD) through acquired mutations in genes. DNMT3A, TET2, ASXL1, and JAK2 genes as well as other genes are the most common somatic mutations causing CHIP and CVD in an older age. Other factors such as cholesterol level, laboratory tests and indexes also affect CVD. In addition, mutations in adenosine triphosphate-binding cassette transporters and also chronic stress in nervous system can result in HSCs proliferation and CVD. However, laboratory tests and indexes are not sensitive for CVD diagnosis. But the therapeutic interventions can be helpful to prevent CVD cases by targeting somatic mutations, chemokine receptors, and growth factors in HSCs. Also, new drugs can control CVD by targeting of cells and their signaling pathways in HSCs. Therefore, more investigations are needed and more questions should be answered for the relationship between CHIP and CVD as a challenging issue in future.

Mixed-phenotype acute leukemia characteristics: first report from Iran.

Mixed-phenotype acute leukemia (MPAL) is the infrequent type of acute leukemia characterized by immunophenotypic and/or cytochemical features of both lineages, but the diagnosis of this disease still is a challenge. In this study, we analyzed immunophenotyping, cytochemistry and frequency of MPAL patients to better diagnosis of MPAL characteristics according to WHO 2016 criteria for the first time in Iran. In this retrospective study, 27 patients were diagnosed as MPAL based on WHO 2016 criteria during 2014-2017. Flow cytometric immunophenotyping was performed on PB and BM samples evaluation of different CD marker expressions in MPAL subsets. RT-PCR was performed for the analyses of BCR/ABL1 fusion in MPAL subsets. Among 27 cases, (70.4%) 19 cases were B + My, (22.22%) 6 cases were T + My, and 2 cases (7.40%) were B + T + My. CD34, CD19, HLA-DR, TdT, CD22, iMPO were positive in majority of B + My cases. CD45, iMPO, iCD3, CD7, CD2 and CD5 were positive in majority of T + My cases. HLA-DR, TdT, CD10, CD22, iCD79a, iMPO, CD45, iCD3, CD7, CD3, CD2, CD5 were positive in majority of B + T + My cases. BCR/ABL1 fusion was positive for 3 cases (11.1%) of p190 fusion and 2 cases (7.4%) of p210 fusion in B + My cases. WHO 2016 criteria are the current standard for diagnosing MPAL. Also, evaluation of TdT, CD2, CD5, CD7 expressions by flow cytometry in EGIL criteria is useful for the better diagnosis of MPAL subsets. In addition, evaluation of BCR/ABL1 and MLL rearrangements in patients should be part of standard work-up in MPAL.

Mutations and Common Polymorphisms in ADAMTS13 and vWF Genes Responsible for Increasing Risk of Thrombosis.

BACKGROUND AND OBJECTIVE: ADAMTS13 (A Disintegrin-like and Metalloproteases with Thrombospondin type-1 repeats, member-13) plays an important role in vascular hemostasis by cleaving the von Willebrand Factor (vWF). ADAMTS13 and vWF are involved in the development of ischemic heart disease. In this review paper, we examine the effects of Single Nucleotide Polymorphisms (SNPs) and mutations in the vWF and ADAMTS13 genes and their contribution to the development of thrombosis. METHODS: Relevant English-language literature was searched and retrieved from PubMed search engine (2001-2017). The following keywords were used: "ADAMTS13", "vWF", "Polymorphism", and Thrombosis". RESULTS: SNPs in the ADAMTS13 and vWF genes cause genetic variability and affect the plasma levels of these genes. Moreover, environmental (such as age, smoking, hypertension) and genetic factors (like ABO blood groups) play a role in the development of different polymorphisms in ADAMTS13 and vWF genes. CONCLUSION: The increased or decreased activity of these two genes as a result of genetic changes and the development of thrombosis are a challenging and contradictory matter, and the study of genetic variability in ADAMTS13 and vWF genes may be helpful in the diagnosis of thrombotic disorders.

Sex chromosome changes in leukemia: cytogenetics and molecular aspects.

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.

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

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.

Role of stem cell factor in the placental niche.

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.

Bone marrow niche in the myelodysplastic syndromes.

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.

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

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.

The Role of HDACs as Leukemia Therapy Targets using HDI.

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.