Paper Example on DNA Methylation in Myeloproliferative Neoplasms

Published: 2021-07-19 17:04:18
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Carnegie Mellon University
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Literature review
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By definition, DNA methylation is an epigenetic mechanism that is essentially used by body cells for the control of gene expression. Although there are numerous mechanisms available for the control of gene expression, the DNA methylation is considered one of the commonly used epigenetic signaling tools since it can fix genes that are considered to be in the off position (Tefferi, 2011). In many occasions, the DNA methylation process is used to affect the interactions with the DNA of both chromatin proteins and specific transcription factors. For instance, this kind of methylation is used in gene expression especially in essential thrombocythemia, polycythemia vera and myelofibrosis commonly referred to as myeloproliferative neoplasms (MPNs) (Mascarenhas, 2017). MPNs are common clonal malignant disorders that are characterized by the increased proliferation of myeloid cells that are terminally differentiated. Usually, these clonal malignant diseases are said to arise from what is considered as the transformation of hematopoietic stem cells or progenitors (HSCs/HPs) which are characterized by the overproduction of mature erythrocytes, megakaryocytes, and granulocytes.

According to recent literature, the World Health Organization classification of 2008 substantially classified these three types of disorders as classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Additionally, the molecular pathogenesis of these MPNs is commonly associated with recurrent acquired mutations in what is referred to as Janus kinase 2 (JAK2) as well as the myeloproliferative leukemia virus oncogene (MPL). Thus, with these kinds of discoveries, the diagnostic approach used for these disorders has been simplified. Besides, these discoveries have also provided various clues necessary for understanding the common phenotypic expression of MPNs.

With reference to the gene expression, control and prognosis of DNA Methylation are considered a heritable epigenetic mark that involves the covalent transfer of a methyl group to the C-5 position of the cytosine ring of DNA by the DNA methyltransferases (DNMTs). In mammals or even human beings at large, the process of DNA methylation occurs at cytosines in any particular context of the genome (Cedar, 1984). Nonetheless, more than 98% of DNA methylation usually occurs in a CpG dinucleotide context in somatic cells. Thus given the critical role played by DNA methylation in both gene expression and cell differentiation, studies substantiate that any possible errors in the methylation process could result in various diseases. However, modern day research on DNA methylation and disease focuses on its applicability in the suppression of cancer and tumors. In this regard, tumor suppressor genes are usually silenced in cancer cells due to the hypermethylation (Vannucchi, et al., 2009).

With regard to the role played by DNA methylation, research has it that an epigenetic mechanism occurs through the addition of the methyl group to DNA and hence modifying the function of the genes. In the process of differentiation, the hematopoietic stem cells (HSCs) essentially give rise to multipotent progenitors which in turn, undergo the commitment to mature cell lineages of the human blood. According to Guillemot, Cimmino & Aifantis, the maturation stages of this malignant hematopoiesis are often characterized by dynamic changes in gene expression that are governed by the transcription factor networks through distinct DNA methylation patterns. With regard to the dynamics of DNA methylation, studies have it that the growth and development of large-scale DNA methylation mapping substantially uncover the dynamism which characterizes the methylome during cell differentiation and transformation (Guillamot, Cimmino, & Aifantis, 2016).

According to Nischal et al. (2012), a majority of the genes that are mutated in MPNs are commonly the same genes that are involved in the regulation of different epigenetic mechanisms. Also, because the epigenetic machinery is one of the key targets of genetic changes in MPNs, numerous studies hypothesize that the presence of these neoplasms alters the epigenome.

Despite the fact that Polycythemia Vera (PV) Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are stem cell derived disorders, they are designed in a clonal architecture that gives them a complex hierarchy that is not always predictable. According to research, the disease course of these disorders is generally chronic. However, some of the patients show inherent tendencies for transformation into acute leukemia which according to Perez et, al. (2013), is a major complication characterized by poor prognosis that is hypothetically accompanied by the acquisition of additional genomic lesions. Many at times, most of the genes that are mutated in MPNs are usually involved in the regulation of different epigenetic mechanisms. Besides, owing to the fact that the epigenetic machinery is considered one of the main targets of genetic changes in myeloproliferative neoplasm (MPNs), it is hypothetical that the epigenome is altered in these neoplasms. Additionally, the epigenetic changes are defined as reversible modifications which substantially affect the gene expression without having to alter the DNA sequence itself. In a similar regard, despite the fact that a lot of advances have been made in the diagnosis of MPNs as well as the description of new molecular markers, there is very little research done concerning the molecular mechanism involved in the pathogenesis of MPNs as well as their Leukaemia transformation. Modern day literature has it that the identification of new markers for both the diagnosis and prognosis of MPNs is essential for the identification of the best molecular targets for therapy (Jin, Li & Robertson, 2011).

Philadelphia Chromosome Negative Classic MPNs

Mascarenhas et, al. (2011) contend that the MPN is often characterized by a hyperproliferative bone marrow and the excessive production of myeloid cells. For patients suffering from polycythemia vera (PV), Essential thrombocythemia (ET) or even primary myelofibrosis (PMF) they usually are at the risk of transformation to acute leukemia and are hence vulnerable to the serious threat of both morbidity and mortality. However, despite the fact that elevated peripheral blood counts typify ET and PV, the primary myelofibrosis (PMF) is different in the sense that, it is usually characterized by anemia and thrombocytopenia (Verstovsek et al, 2006). On the other hand, the polycythemia vera is defined by the increase in the red cell mass, typically in the absence of conditions which induce secondary erythropoiesis as well as specific diagnostic criteria that are commonly used in aiding in diagnosis confirmation. Studies substantiate that patients suffering from PV usually have a 1.6-fold higher mortality than the control population with the main causes of both morbidity and mortality. With regard to the prognosis, there is proof that PV arises from a multipotent hematopoietic stem or progenitor cells. According to Verstovsek et al. (2006), an approximated 95% of PV patients express the JAK2V617F mutation.

Essential ThrombocythemiaEssential thrombocythemia is an indolent clonal hematological neoplasm. As a myeloproliferative disorder, ET is characterized by an increased platelet count, a hemorrhagic, megakaryocytic hyperplasia, or thrombotic tendency. Unlike the other two MPNs, the JAK2 V617F mutation is identified in almost half of the patients. According to the 2008 WHO classification update, Essential thrombocythemia (ET), is the most common MPN disorder in the United States. According to studies done in the recent past, unlike other MPN disorders, ET is defined by a platelet count that is essentially greater than 450, 000 x 10^9/L, usually in the absence of other MPN. As a disorder, patients suffering from ET are characterized by a similar age matched median survival for the first ten years after diagnosis which after that shorten secondary to thrombosis or hemorrhage. According to research, approximately 50% of patients with ET, JAK2V617F is expressed and in comparison to PV with a lower allele burden.

The Pathogenesis of Essential ThrombocythemiaResearch has it that one of the primary milestones that are necessary for understanding the MPN pathogenesis is the identification of the acquired Janus kinase 2 (JAK2) V617F mutation. Usually in an average of 50-60% of the patients suffering from ET, the detection of this molecular lesion from either the patients bone marrow cells or the peripheral blood cells is very crucial for diagnosis. In this regard, JAK is considered as an essential protein that is involved in intercellular transduction of signals that are known to originate from the thrombopoietin receptor through the JAK-STAT pathway. Moreover, various studies suggest that a majority of positive JAK2 V617F cases usually share some common features with PV. Some of these features are such as higher hemoglobin values, more frequent incidences of fibrotic marrow transformation, more thrombotic complications and also higher numbers of neutrophils. However, studies done in the recent past suggest that two molecular lesions have been identified in Essential Thrombocythemia (ET) and PMF patients who contribute to the primary understanding of the disease pathogenesis as well as the diagnosis process.

With regard to the pathogenesis of this disorder, the calreticulin (CALR) gene mutation is possibly detected in approximately 15-24% of ET patients who are often considered JAK-2 V617F negative. Besides, in ET, mutant CALR is usually associated with young patients of a younger age and specifically of the male gender with lower leukocyte and hemoglobin values with higher numbers of platelets and decreased risks for thrombotic events.

Treatment of Essential ThrombocythemiaOwing to the fact that ET is a chronic hematologic malignancy, it is important that patients regularly consult with a hematologist and also report any kinds of symptoms such as visual disturbances, bruising, numbness or even unusual pains. While at least 50% of patients with ET are asymptomatic mainly at the time of their diagnosis, research suggests that a majority of these patients will develop vasomotor, hemorrhagic or even thrombotic manifestations at some point in the course of this particular disorder (Beer & Green, 2009). This being the case, healthcare professionals, therefore, contend that those patients who receive immediate treatment. Studies done on the prognosis and treatment of this particular disorder substantiate that some of the most common symptoms of the disease include splenomegaly, general body weakness, headaches, bleeding, and paraesthesia, among others. According to scholars, one of the most common treatments for this disease includes the lowering of the platelets count. However, it is advisable that potentially toxic drugs that are known to lower the platelet count in the body should not be used in asymptomatic patients. According to research done by the Mayo Clinic, there are various agreed-upon indications for the platelet count lowering therapy.

The Pathogenesis of Primary MyelofibrosisUnlike the other two MPN disorders, primary myelofibrosis, also known as chronic idiopathic myelofibrosis is a common disorder that occurs in the bone marrow. Besides, despite the fact that primary myelofibrosis (PMF) has a markedly worse prognosis than the rest of the MPNs, essential thrombocytes and polycythemia vera, the molecular distinctions between these subgroups are not effectively elucidated. Usually, the bone marrow tissue replaces itself with a fibrous scar-like material which in turn progresses to what is referred t...

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