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MOLECULAR AND GENETIC RISK FACTORS FOR THE DEVELOPMENT OF
THROMBOTIC AND HEMORRHAGIC COMPLICATIONS IN ESENTIAL
THROMBOCYTHEMIA
(Literature review).
Musashaykhova Sh. M., Musashaykhov U. Kh.
Andijan State Medical Institute.
Report.
Essential thrombocythemia (ET) is a pathology of clonal hematopoietic stem cells that
leads to increased platelet production. Pathogenetically, ET is a bone marrow disease in which
megakaryocyte proliferation leads to persistent hyperthrombocytosis with the risk of vascular
thrombosis and thromboembolism. The etiology of the disease has not yet been established. The
leading hypothesis is the polyethological nature of the disease occurrence, where the
predisposition to the disease is realized under the influence of external factors that damage the
genome of a normal cell and lead to its malignant transformation
Molecular genetic analysis
of JAK2
V617F,
JAK2
exon12,
MPL
W515K/L, and
CALR mutations
plays an exceptional role in the diagnosis of classic Ph-negative MPN. However, genes that
control signal transmission within the cell, chromatin remodeling, DNA methylation, oncogenes,
and tumor suppressors are involved in the development of these diseases. Current knowledge
suggests that
the JAK2
V617F mutation may not be the first event in the complex pathogenesis of
myeloproliferative diseases (MPD). This review describes the current understanding of molecular
genetic disorders that are risk factors and affect the development of thrombotic and hemorrhagic
complications in ET.
Key words:
chronic myeloproliferative diseases, essential plateletмformation, primary
myelofibrosis, JAK2 gene , MPL gene, CALR gene, triple-negative status.
Essential thrombocythemia (ET) is a chronic tumor myeloproliferative disease of a clonal nature,
characterized by megakaryocyte proliferation and persistent thrombocytosis [3, 2, 20]. ET is a
rare (orphan) disease. There are no population-based epidemiological data on morbidity and
prevalenceёin Uzbekistan. The morbidity rate, according to foreign registries [4, 6, 14], is
approximately 1.5-2.53 per 100,000 population. Classical ideas about ET as a disease mainly of
elderly people with a maximum incidence of 50-60 years are currently being revised. The
discovery of the involvement of molecular genetic breakdowns (mutations in
JAK2, MPL
, etc.) in
the pathogenesis of the disease and the introduction of methods for their determination into
clinical practice made it possible to identify a significant proportion of young patients [8, 29]. The
ratio of women to men is approximately equal. However, there are slightly more women than men
among young patients [35].
The main reason leading to disability and reduced life expectancy in ET is the development of
thrombosis and thromboembolism. The cumulative risk of clinically significant thrombosis is 5%
for the duration of the disease of 5 years and 14% for the duration of ET of 10 years [2, 3]. With a
prolonged course of the disease, secondary post-platelet myelofibrosis may occur in 3-10% of
patients during the first 10 years of the disease and in 6-30% of patients with a disease duration of
more than 10 years [31, 23, 32]. Progression of the disease to the blast transformation phase is
observed in 1-2. 5% during the first 10 years of the disease and in 5-8% of patients with a disease
duration of more than 10 years [23, 32, 28].
The etiology of the disease has not yet been established. The leading hypothesis is the
polyethological nature of the disease occurrence, where the predisposition to the disease is
realized under the influence of external factors that damage the genome of a normal cell and lead
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toё its malignant transformation [1, 25, 52, 13]. Hereditary predisposition to the disease may be
due to the carrier of the 46/1 haplotype of the JAK2 gene [10].
The clinical course of the disease is closely related to its pathogenesis. At the initial stage of
development, there is a gradual increase in the tumor mass. During the first years of the disease,
the main manifestations of ET are an increased risk of developing thrombosis and
thromboembolism against the background of existing cardiovascular pathology and
atherosclerosis. Leukocytosis and thrombocytosis can lead to microcirculation disorders and the
development of thrombosis. The occurrence of thrombosis in ET is always the result of the
interaction of changes caused by the disease and multiple risk factors for thrombosis. Factors
contributing to the development of thrombosis can be divided into two groups: [1, 19].
1. Factorsassociated with the disease: thrombocytosis, leukocytosis, interaction between
leukocytes and platelets, biochemical and functional abnormalities in platelets, activationof
theblood clotting process, the presence
of JAK2
V617F mutation and a high allelic load.
2. Individual factors of the patient: age, history of thrombosis, risk of cardiovascular
complications, thrombophilia.
An increase in the concentration of procoagulant microparticles produced by both platelets and
endothelial cells also contributes to the increased risk of thrombosis [49]. The cumulative risk of
clinically significant thrombosis is 5% with a disease duration of 5 years and 14% with a ten-year
history of ET [23].
Uncontrolled activation of the cellular signaling pathway JAK-STAT is a key element in the
pathogenesis of ET. Currently, the central role of somatic point mutation of the gene encoding
tyrosine
kinase JAK2
(
JAK2
V617F)
,
in the activation of the JAK-STAT pathway has been
reliably established. The discovery of the mutation in 2005 and the subsequent study of its role in
the pathogenesis of ET radically changed the existing ideas about the origin and development of
the disease, led to a radical revision of existing ideas about the pathogenesis of the disease, which
made it possible to form a new diagnostic algorithm for ET and contributed to the inclusion of
mutation in the diagnostic algorithm of ET. However, the presence
of JAK2
V617F only in 50-
60% of patients revealed the need to search for other genetic rearrangements involved in the
development of clonal myeloproliferative process
in JAK2
V617F-negative patients. [4].
Activation
of JAK2
kinase, mutation in the MPL thrombopoietin receptor gene
, and loss of
function of the LNK gene of the SH2B3 protein, which inhibits JAK2 activity, may be one of the
key pathogenesis factors and a probable molecular genetic mechanism of ET development
и
потеря функции гена LNK белка SH2B3, ингибирующего активность
JAK2
[51].
Pathogenetically, ET is a clonal myeloproliferative process that develops as a result of malignant
transformation in early hematopoietic progenitors with a violation of cellular signaling pathways
that regulate cell growth, activation, differentiation, adhesion, and apoptosis [13]. A significant
(25-55%) proportion of patients with ET is characterized by the detection of a point mutation in
the januskinase gene of the erythropoietin receptor
JAK2V617F
[16, 25, 42]. Also, some patients
may have mutations in the genes of the thrombopoietin receptor-
MPL
and
TET2
[39, 30],
The diversity of the phenotype of myeloproliferative neoplasms (MPN) is determined by genetic
heterogeneity. Mutations primarily affect genes that control cytokine signaling pathways. The
JAK-STAT pathway plays a crucial role in the proliferation and differentiation of hematopoietic
cells. In patients with MPN, a somatic JAK2 mutation is detected with a high frequency
JAK2
,
most often
JAK2
V617F. Since 2008. The main diagnostic criteria for IP, ET, and PMF included
the presence
of the JAK2
V617F mutation. After the discovery
of JAK2
V617F, other mutations in
the gene were also identified [
38
].
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At the present stage, the role of somatic point mutation of the JAK2 tyrosine kinase gene
(
JAK2
V617F) in the activation of the JAK-STAT pathway in Ph-negative MPN is indisputable.
Mutation detection is central to the diagnosis of ET [47].
Activation of the JAK-STAT signaling pathway is an important pathogenetic event in classical
Ph-negative MPN. In PMF and ET, half of the patients have acquired
the JAK2
V617F mutation.
In addition, other components of the JAK-STAT signal transduction pathway are an important
regulator of hematopoiesis [6].
Thus,
the JAK2
V617F mutation is a specific molecular genetic marker of the clonal
myeloproliferative process in ET. With a comprehensive diagnostic approach, combined with
other criteria, the detection
of JAK2
V617F makes it possible to reliably and reasonably establish
the diagnosis of ET in 50-60% of patients.
However, in the remaining 40-50% of patients, the genetic basis of clonal myeloproliferation
remained unknown. The persistence of a significant number
of JAK2-
negative patients, whose
disease genesis remained poorly understood, revealed the need to search for new molecular
genetic markers of clonality in this category [5].
Current knowledge suggests that
the JAK2
V617F mutation may not be the first event in the
complex pathogenesis of ET. Additional studies are needed to clarify the role of other molecular
events in the formation of the phenotype of each individual nosology in the Ph-negative MPN
group. The new data are of indisputable importance for the synthesis of targeted drugs.
As a result of the search for other molecular genetic markers of clonality, two types of somatic
mutations were identified that are also involved in the activation of the JAK-STAT pathway. In
2006, somatic mutations of the thrombopoietin receptor gene
, MPL, were described
, and in 2013,
mutations of the gene encoding the protein calreticulin,
CALR
. The study of the effect
of MPL
and
CALR mutations
on the pathogenesis of ET is currently ongoing.
Another gene involved in the regulation of the JAK-STAT signaling pathway is the
thrombopoietin receptor gene. Binding of thrombopoietin to this receptor regulates
megakaryocyte maturation and platelet lacing by activating the JAK-STAT pathway [24].
Мутации
MPL mutations
(most commonly W515L) have been described in patients with PMF
and ET.
The thrombopoietin receptor (
MPL
) gene belongs to the cytokine receptor superfamily, located on
chromosome 1p34 and includes 12 exons. Thrombopoietin, after binding to the extracellular
domain of the receptor, causes phosphorylation and activation of tyrosine kinase JAK2,
phosphorylation and activation of MPL, and signal transmission via the STAT pathway. Studies
have shown that the level of MPL receptor expression is important for the onset and progression
of MPN [18,37].
Mutations
of the MPL gene
do not occur in patients with ET, but can be detected in patients with
secondary acute myeloid leukemia (AML). They can occur both in isolation and together with
JAK2
V617F with a higher allelic load
of the MPL mutation
. The frequency of detection
of
MPL
W515L and
MPL
W515K mutations in patients with PMF and ET is 1-15% [12, 7].
In the presence
of the MPL mutation
, the disease is characterized by high thrombocytosis, normal
erythropoietin levels, low hemoglobin content, and low bone marrow cellularity.
The MPL
mutation
compared to
JAK2
V617F is a more significant risk factor for thrombotic complications
and the development of transfusion-dependent anemia [12, 48]. The association between
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splenomegaly, abnormal karyotype, risk of transformation of the disease into post -platelet
myelofibrosis (MF) or AML and the presence of mutations
in the MPL gene has not been proven
.
Nevertheless, clinical cases have been described where a high risk of thrombosis, massive
splenomegaly, and bone marrow fibrosis was observed in familial thrombocytosis caused by the
Ser505Asn mutation
of the MPL gene
[4-8]. Although patients with
MPL
W515K also have a high
allele load compared to
MPL
W515L, there were no significant differences in clinical and
laboratory characteristics in these groups [12].
In most cases, the difficulties of studying the effect of mutations in
the MPL gene
on the course of
ET are related to their rarity. Patients with three mutations (TN-status) remain the least studied
category. The prognosis in patients with TN is currently recognized as unfavorable.
The discovery
of CALR mutations
plays an important role in the molecular diagnosis of MPN.
JAK2
V617F
, CALR
, and, more rarely,
MPL
are the main clonal markers of MPN [43]. It should
be noted that
CALR mutations
were detected in 2 cases
of JAK2
-negative true polycythemia (IP)
[15]. In addition, assessment of the mutational status
of JAK2, MPL
, and
CALR
is important not
only for diagnosis, but also for prognosis of both thrombotic complications and overall survival
[44].
Somatic mutations in the CALR gene were detected in 30-45% of MPN patients with the absence
of JAK2
and
MPL CALR
mutations. Patients with
CALR mutations
have a different disease
phenotype from
those with JAK2
,
MPL
, or triple-negative mutations. ET occurs with a lower level
of hemoglobin and the number of white blood cells, higher thrombocytosis and a low risk of
thrombosis, and a high risk of post-platelet-induced MF. Patients are usually young, mostly male
[22]. Family cases of ET with
the CALR mutation
are characterized by high thrombocytosis and a
low rate of disease progression compared to cases with
the JAK2 mutation
[36].
Conflicting data have been obtained on the effect
of the CALR mutation
on the survival of ET
patients. Better overall survival is reported in the group of patients with
the CALR mutation
compared to patients with Alzheimer's disease.
with
the JAK2 mutation
[22]. In the study conducted by J. Nangalia, no statistically significant
differences were found [26].
In PMF patients
, CALR mutations
were associated with high thrombocytosis, normal white blood
cell count, low anemia rate, and transfusion dependence on red blood cell suspension transfusion.
The disease was mainly diagnosed at a young age, and patients were classified as low-risk
according to the DIPSSplus scale [45].
ET in the presence of mutations in
the JAK2
and/or
CALR genes
— biologically, clinically and
prognostically different forms of the disease. In ET, the presence
of the JAK2
V617F mutation
increases the risk of thrombosis. Despite the fact that the carriage of mutations in
the CALR gene
is associated with significantly more pronounced thrombocytosis (platelets > 1000 ×
109
/L) [26],
the risk and frequency of thrombosis in this category of patients is lower than in ET patients with
the JAK2
V617F mutation. Patients with ET who carry mutations in
the CALR gene
are
characterized by a decrease in the risk and frequency of thrombosis, and the course of the disease
can be characterized as indolent [53, 9].
Thus, molecular genetic analysis
of JAK2
V617F,
JAK2
exon12,
MPL
W515K/L, and
CALR
mutations
plays an exceptional role in the diagnosis of classic Ph-negative MPN. However, genes
that control signal transmission within the cell, chromatin remodeling, DNA methylation,
oncogenes, and tumor suppressors are involved in the occurrence and development of these
diseases [27].
In addition to three somatic mutations (
JAK2
V617F
, MPL
, and
CALR
) that activate the JAK-
STAT pathway, ET revealed a spectrum of different epigenetic rearrangements:
TET2, EZH2,
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ASXL1, CBL, IDH, IKZF1, LNK, and IDH1/IDH2
. Somatic mutations
of the TET2, EZH2
,
DNMT3A
,
DNMT3A
and
ASXL1 genes
play a significant role in the pathogenesis of MPN and
determine the phenotype and prognosis of the disease. Somatic mutations can occur prior to the
appearance of a clone with
the JAK2 mutation
, simultaneously, or as a late molecular event during
disease progression [21].
The lack of convincing data in favor of the specificity of such mutations for ET, their detection in
other diseases of the blood system, organs of lymphoid and hematopoietic tissues:
myelodysplastic syndrome (MDS), acute leukemia (OL), lymphoproliferative diseases
(lymphomas), does not allow us to talk about the pathogenetic role of these rearrangements and
their inclusion in the diagnostic algorithm of ET in as highly specific molecular genetic markers
of clonality. However, the contribution of epigenetic mutations to the emergence and
development of ET requires further study.
The TP53 gene encodes a tumor suppressor protein involved in regulating the expression of target
genes that regulate the cell cycle, apoptosis, and DNA repair. Loss of gene function is associated
with the appearance of various human malignancies. Mutation of the TP53 gene was detected in
45.5% of MPN in the blast crisis phase and only in 4% in the chronicоphase [34]. Thus, TP53
mutations play an important role in the process of disease transformation.
Thus, molecular genetic analysis
of JAK2
V617F,
JAK2
exon12,
MPL
W515K/L,
CALR
, and TP53
mutations plays an exceptional role in the diagnosis of classic Ph-negative MPN. However, genes
that control signal transmission within the cell, chromatin remodeling, DNA methylation,
oncogenes, and tumor suppressors are involved in the development of these diseases. Current
knowledge suggests that
the JAK2
V617F mutation cannot be the first event in the complex
pathogenesis of MPN [15].
However, despite modern advances in understanding the etiology and pathogenesis of the disease,
there is currently no empirically confirmed, unified and generally accepted concept of the
pathogenesis of ET. The leading hypothesis of the pathogenesis of the disease is polyethological.
Predisposition to the development of ET, as well as other diseases of the Ph’-negative MPN group,
is realized when the hematopoietic stem cell is exposed to various external factors that damageё
its genome with subsequent malignant transformation of the cell [41, 42]. Under the
predisposition, the carrier of various genetic changes is considered. Thus, carriage of haplotype
46/1
of the JAK2 gene
is associated with a significant increase in the risk of V617F rearrangement
in
the JAK2 gene
[11, 41].
Additional studies are needed to clarify the role of other molecular events in the formation of the
phenotype of each individual nosology in the Ph-negative MPN group. The new data are of
indisputable importance for the synthesis of targeted drugs.
External agents, the action of which causes the appearance of clonal rearrangement of a normal
cell, are factors of a physical and chemical nature, various viral and bacterial agents. At the same
time, the action of external damaging factors can provoke the development of chronic
inflammation. The inflammatory process, in turn, is a stimulator of hematopoiesis and, including,
myelopoiesis. In addition, a prolonged inflammatory process increases the risk of cell DNA
damage, which may also be one of the reasons for the appearance of genetic defects in
hematopoietic cells [21]. At the same time, chronic inflammation is manifested by increased
production of pro-inflammatory cytokines. Prolonged increases in cytokine concentrations also
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contribute to damage to the cellular genome. Thus, a chronic autoimmune or inflammatory
process accompanied by an increased concentration of cytokines in the blood is a factor
contributing to the development of ET in predisposed individuals [50].
The influence of external factors combined with the presence of a genetic predisposition is
realized in the appearance of a genetic disorder – a mutation at the level of a polypotent
hematopoietic progenitor stem cell. As a result of the genetic rearrangement that triggers the
myeloproliferative clonal process, a clone of myeloid hematopoiesis progenitor cells is formed.
Unfortunately, at present we can only talk about probable genetic events responsible for the
development of malignant transformation of a normal hematopoietic stem cell. There are no
convincing experimental data that allow unambiguously accepting any of the known gene
mutations as a pathogenetic event that initiates the clonal process [2, 1, 33, 17].
At the present stage, the question of the possible influence of somatic mutations
of the JAK2,
MPL
, and
CALR genes
on the clinical course and prognosis of ET remains open. The data
published in various literature sources do not allow us to make a complete and systematic
description of the development, clinical course, and prognosis of ET in carriers of various genetic
rearrangements. In addition, possible combinations of somatic mutations with epigenetic
rearrangements and chromosomal aberrations, their impact on the course, risks of complications,
and modification of the prognosis of the disease need to be studied.
In recent years, significant progress has been made in deciphering the molecular and genetic
mechanisms of ET, which has made it possible to create a new class of drugs with pathogenetic
effects.
The goal of modern ET therapy is to prevent vascular catastrophes, control the progression of the
disease and stop its symptoms, while improving the quality of life of patients [40].
Adequate diagnosis and regular monitoring of treatment using clinical, morphological,
cytogenetic and molecular genetic research methods is a prerequisite for correct prediction of the
course of the disease and achieving maximum effectiveness of therapy. Currently, there are no
generally accepted standards for the diagnosis and treatment of ET in Russian clinical practice.
Therefore, thestudy of ET should be continued in order to identify and describe new specific
molecular genetic markers of clonality, which may contribute to a deeper understanding of the
nature of this malignant myeloproliferative disease.
It seems appropriate to study the impact of genetic rearrangements on the clinical course, possible
potentiation of the risks of complications, and the overall prognosis of ET.
The data available in the literature on the role of these individual genetic markers are few and
contradictory. Only a detailed study of the population features of the above-mentioned genetic
mutations and an assessment of the correlation between the genotype and phenotype of the
disease can make it possible to choose the right strategy for early diagnosis and prognosis, as well
as the development of preventive measures for thromboembolic and hemorrhagic complications in
patients with ET. Unfortunately, there are still quite rare publications in which the authors analyze
the so-called risk factors for the development of the above-mentioned complications in ET.
Finally, there are many unresolved questions regarding the feasibility of diagnosing certain gene
polymorphisms in clinical practice, which is largely due to the insufficient number of studies
aimed at establishing correlative relationships between the features of the clinical course of ET
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and the presence of certain markers in the patient's genotype. The question of which interactions
of acquired and genetic factors, as well as gene-gene combinations, determine the predisposition
to the development of thrombosis and hemorrhage, and the features of the course remains open.
The need to use fundamentally new approaches in studying the basis of genetic predisposition to
such types of complications in ET is dictated by the current concept of the polygenic nature of
myeloproliferative diseases, which postulates the presence in the vast majority of cases of
thromboembolic diseases of not one, but several genetic variants that independently or
synergistically modify the risk of developing the disease.
The obtained data will improve the assessment of the clinical and prognostic significance of the
carriage of molecular genetic rearrangements in ET and will contribute to updating therapeutic
approaches and algorithms, which will optimize the treatment and personalize the tactics of
therapy for this disease.
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