More than 100 groups of distinct disease characterized by the abnormal and uncontrolled growth of the cells within the body. Cancer is considered to be a major cause of sickness throughout the world, and it affects one in every three persons born in the developed world (Bishop & Weiberg, 1996). Though it has been known since a long time ago, important improvements in cancer treatment have been made since the middle of the 20th century only, mainly through a combination of timely and accurate diagnosis, selective surgery, radiation therapy, and chemotherapeutic drugs. These advances towards the diagnosis and treatment of cancer has reflected positively on the reduction of mortality caused by this disease, furthermore, the laboratory investigations are promising for further explanation of the cause and the mechanisms of this disease. Researchers have established a fundamental understanding of what is the defect occurred in a cancer cell through the continuing advances in cell biology, genetics, and biotechnology.
Causes of cancer:
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The massive number of cells that make up the tumour is derived from one cell that had a way to escape the normal control of its growth. The absence of the control is caused by a damage in the genetic material of the cell, particularly the long, coiled chains of the DNA found in the chromosomes (Bishop & Weinberg, 1996). This damage can occur during cell division, and can be triggered by different mechanisms such as environmental agents, or it might be inherited. Eventually this genetic changes and other abnormality is passed into the offspring of the original abnormal cell, this transport of genetic material occurs regardless of how the damage was caused in the first place (Bowen & Bowen, 1990).
Constantly cells are faced with decision, these decision involve either to proliferate (divide), differentiate (by expressing specialized properties that differentiate one organ from another), or die. About 100 genes from enormous genes that make up the human body are involved in these decisions (Yarnold et al., 1996).
Growth of the cells is regulated by different genes which can be divided into two categories according to their activities, either encouraging cell growth which are known as 'proto-oncogenes', or inhibition of the growth, these are known as 'tumour suppressor genes' (Peters & Voundsen, 1997). Many external factors that are known to contribute in causing cancer like viruses, chemicals and radiation are exerting their effect on these genes by inducing changes on them or by interfering with the function of the proteins that are encoded by these genes (Peters & Voundsen, 1997). Tumour suppressor genes mutations involve elimination of necessary brakes on cell growth, whereas mutations in proto-oncogenes tend to over stimulate cell growth.
The myeloproliferative disorders (MPDs) or what recently renamed as myeloproliferative neoplasms, are a group of pre-leukaemic disorders that involve abnormal proliferation of one or more lineages of the myelo-erythroid series (Bench, 2001). They include, Polycythemia Vera (PV), Essential Thrombocytosis (ET) and Myelofibrosis (MF). William Dameshek was the first to name this group of disorders as myloprolifrative disorders in 1951. He grouped them together along with chronic myeloid leukaemia (CML), but because CML has a different pathogenomic chromosomal translocation, a greater clinical homogeneity and an increased leukemic potential, it is considered as a separate entity (Provan & Gribben, 1999). However, MPDs have the potential to transform into Acute Myeloid leukaemia in some patients.
Frequency of MPDs
They are comparatively uncommon disorders. According to a Swedish study by Kutti et al., (2001), the annual incidence of Polycythemia Vera is 2.8 per 100,000 while essential thrombocythemia has an incidence of 1.5 per 100,000 per year. Myelofibrosis has the lowest international incidence of 0.4 per 100,000 per year (Kutti et al., 2001). The actual incidence is difficult to measure since many people affected are asymptomatic until the occurrence of a major consequence such as a thrombosis or stroke.
The severity of an MPD varies from patient to patient. It may be presented as an acute life threatening condition or sometimes it may be asymptomatic in other patients lasting for years before being diagnosed coincidentally during a routine examination. Each one of the three most common MPDs has its own set of symptoms, but they frequent share the following in common signs and symptoms;
Always on Time
Marked to Standard
Weakness and fatigue
Enlargement of theÂ spleenÂ (splenomegaly)
Bleeding and bruising, due to insufficient and/or abnormal platelets
Bone and joint pain
PallorÂ due toÂ anaemiaÂ
Chromosomal abnormalities are seen in approximately one third of patients with PV and IMF. In ET, the detection of chromosomal abnormality is infrequent. Some chromosomal changes such as deletions or monosomies of chromosomes 5 and 7 are almost invariably seen after exposure to myelosuppressive therapy and often as part of complex karyotype. Is is hence improbable that these chromosomes contain genes involved in the aetiology of MPDs. By contrast, deletions of part of the long arm of chromosomes 20 (del 20q) and 13 (del 13q), trisomies of chromosomes 8 and 9 and duplication of part of the long arm of chromosome 1 have been seen in untreated patients and are frequently present as the only abnormality. Therefore, they are likely to mark the site of genes that play an early role in the pathogenesis of the MPDs (Provan & Gribben, 2000).
This deletion was noted to be important in 1993, when a study done by Dewald and colleagues. In their study they observed that out of 3996 abnormal bone marrow samples about 3000 samples had a single chromosomal abnormality and out of these del(20q) was the second most common abnormality after t(9;22). This deletion is not only seen in MPDs. It is also in almost 4% of patients with myelodysplastic syndromes (MDS) and in 1-2% of patients having AML but rarely seen in lymphoid malignancies (Asimakopoulos et al., 1996). There was no any significant survival rate in MPD patients with or without the 20q deletion. The common deletion region in MPD spans a distance of 8-9 mega base pair and it is considered a larger region compared to the one in MDS, which has a region of 7-8 mega base pair (Provan & Gribben, 2000).
La Starza et al. studied the 13q deletion in myeloid malignancies, in 1998. They identified a common deleted region of 4 centiMorgans in MDS patients and of 14 cM in MPD patients (La Sterza et al., 1998). This deletion is found in 10% of the PV cases and in 6% of the Idiopathic myelofibrosis cases (Atlas of Genetics and Cytogenetics in Oncology and Haematolog, online).
Duplication of Segments of 1q
Dupl. (1q) in MPD originates within the multipotent progenitor and this was confirmed by the observation that it has been found in both erythroid and myloid precursors of an MPD patient. It is also found at all stages of disease progression, including at diagnosis. It has been identified that has a common duplication region spanning 1q23-q32.
Trisomy 8 and 9
The detection of Trisomy 8 and 9 was done by using FISH-based techniques, using centromeric probes and chromosome paining. Using this technique allowed the observation of interesting findings.it has been observed that cells with Trisomy 8 have a proliferative advantage over normal cells (Sloand et al., 2003). Like for the del (20q) Trisomy 8 arises in primitive progenitor cells with myeloid and lymphoid potential.
Molecular Pathophysiology of MPDs
The most common MPDs are considered Philadelphia-negative chronic myeloproliferative disorders, unlike chronic myeloid leukaemia (CML). They areÂ characterized by various combinations of erythrocytosis, leukocytosisÂ and thrombocytosis. These conditionsÂ are typical clonal disorders of hematopoietic stem cells. TheÂ occurrence of a mutation ofÂ JAK2 orÂ MPL6 inÂ a multi-potent stem cell generates a myeloid clone that expandsÂ to replace hematopoietic cells without the mutation.Â This cloneÂ is more capable in the production of mature blood cells, atÂ least initially, and this results in increased peripheral bloodÂ cell counts.
The clearer picture of the molecular pathogenesis of Philadelphia chromosome negative MPD was obtained when Fialkow and colleagues (1967) studied female CML patients with polymorphisms at the G6PD locus. They concluded that a single G6PD isoform was present in all red blood cells and granulocytes, consistent with clonally derived myelopoiesis. The same stratigy was used In 1976 by Adamson, Fialkow, and colleague to demonstrate a single G6PD isoform in red blood cells, granulocytes, and platelets from patients with PV, consistent with panmyeloid clonal expansion (Fialkow et al., 1976). This was followed by other studies using polymerase chain reaction (PCR)-based assays that confirmed the first observation. However, analysis of recurrent cytogenetic alterations, in particular deletions on the long arm of chromosome 20, shows that clonal alterations can occur in MPD cells with multilineage potential (Asimakopoulos et al., 1996). All these studies show that PV, ET, and PMF actually originates in a multipotent hematopoietic progenitor, despite the predominant lineage involved in the clinical phenotype (Ross et al., 2008). Next, Prchal and Axelrad made another observation when they noted that in vitro culture of bone marrow cells from PV patients, but not from normal volunteers, resulted in erythroid colonies without the presence of exogenous cytokines.
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In 2005, the observations of Dameshek, Fialkow, Adamson, and Prchal was correlated with the identification of the JAK2V617F allele in the most of patients with PV, ET, and PMF (Baxter et al., 2005). A variety of genetic, functional and genomic approaches allowed researchers to identify the identical mutation in JAK2 in these disorders. A study done by William Vainchenker and colleagues observed that small molecule or siRNA mediated inhibition of JAK2 in PV hematopoietic progenitors abrogated endogenous erythroid colony (EEC) formation (Ugo et al., 2004). This observation gave them a indication to examine JAK2 for mutations in PV. To identify the JK2V617F allele in PV, ET and PMF, Anthony Green and colleagues used candidate gene resequencing followed by allele-specific PCR (Baxter et al., 2005). Based on the observation of Josef Prchal and colleagues that acquired uniparental disomy (UPD) of chromosome 9p24 is common in PV, Robert Kralovics, Radek Skoda, and their colleagues sequenced the genes in the minimal region of UPD to identify the JAK2V617F allele (Kralovics et al., 2005). Levine and colleagues used an approach based on the previous identification of activating mutations in tyrosine kinases in other MPDs, and performed a systematic survey of the tyrosine kinome in PV using high throughput DNA resequencing that resulted in the identification of the recurrent mutation in JAK2 in MPD (Levine et.al., 2005).
The mutation in JAK2 is a guanine to thymidine substitution that results in a valine to phenylalanine substitution at codon 617 of JAK2. The mutation is not present in the germ line, keeping in mind that JAK2V617F is acquired as a somatic disease allele in the hematopoietic compartment. Until now, no other mutations have been described at this codon in MPD or in other human malignancies. This is shocking, especially in light of a recent report demonstrating that substitution of any of 4 alternative residues (tryptophan, methionine, isoleucine, and leucine) for valine at codon 617 leads to JAK2 activation and in hematopoietic transformation in vitro (Ross et al., 2008). Other activating mutations that activate JAK2, including the T875N kinase domain mutation, the IREED deletion and the less common JAK2 exon 12 mutations have been observed in patient samples and in cell lines although each of these alleles is extremely rare in frequency compared with JAK2V617F. Although JAK2 signalling is basically activated by a variety of genetic and epigenetic mechanisms in human malignancies, including lymphoma and myeloma,36,37 the JAK2V617F allele is exclusive to myeloid malignancies (Glam et al., 2003), suggesting there are different mechanisms that activate JAK2 in different neoplasms.
A high proportion (> 50%) of patients with myeloproliferative disorders carry a dominant gain-of-function V617F mutation in the JH2 kinase-like domain of JAK2. This mutation leads to deregulation of the kinase activity, and consequently to constitutive tyrosine phosphorylation activity. The V617F mutation in different studies ranges from 65-97% in polycythemia vera, from 41-57% in patients with essential thrombocythemia, and from 23-95% in patients with idiopathic myelofibrosis (Baxret et al., 2005). In MPD the mutation is heterozygous in most patients and homozygous only in a minor subset. Mitotic recombination probably causes both 9p LOH and the transition from heterozygosity to homozygosity.