Page 72 - GTM-3-2

Global Translational Medicine Genes and blood cells in Ph-negative MPNs

thrombotic complications. It can be speculated that the is important in the regulation of hematopoiesis, and the
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higher counts of PLTs and WBCs observed in JAK2V617F detection of genetic abnormalities in it is associated with
mutation-positive patients with ET in our study may result the development of myeloid neoplasms. 41,42 The EXOC3L2
in such neutrophil-PLT aggregation. gene (19q13.32), which belongs to the regulators of PLT
PLTs retain high levels of active PAI-1. The concentration quantitative parameters, is located next to the cluster
of PAI-1 in plasma has been found to correlate with the of a large family of genes PRV (CD177) and Ly6/uPAR
number of PLT in the blood. In fact, more than 50% of (19q13.31), which form one functional block, whose
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PLT PAI-1 is in the active form. Since PLTs retain mRNA overexpression is typical for PV and ET. The significance of
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from megakaryocytes and have the ability to synthesize uPAR in maintaining normal PLT survival is noteworthy. 43
certain proteins, they can synthesize PAI-1 de novo. In vitro Thus, the genes responsible for the expression of uPA-
studies have demonstrated that the amount of PAI-1 uPAR-PAI-1/PAI-2, PLT quantitative parameters, and JAK-
synthesized in 24 h is 35 times higher than that required to STAT signaling pathway proteins share several common
maintain normal plasma levels. 32 chromosomal regions (1p34.1-p34.3, 7q21.1-q21.3,
It is more common for patients with clonal 9p24.1, 19p13.11-p13.2, and 19q13.31-q13.32). Due to
thrombocytosis to experience thrombosis than for this close spatial location, these genes can form specific
those with secondary thrombocytosis. In cases of clonal genetic complexes and mutually influence their expression
thrombocythemia, plasma levels of PAI-1 antigen and levels through genetic regulation and gene interactions.
activity are significantly higher than in the reactive Given that phenotypic features of tumors are determined
thrombocytosis group. Given that PLTs continuously by many genes, a comprehensive study of mutations and
produce substantial quantities of active PAI-1 and gene dysregulation in the above-mentioned chromosomal
represent the primary reservoir of PAI-1 in plasma, the regions will not only contribute to a better understanding
thrombotic tendency observed in MPNs may be associated of the molecular genetic nature of Ph-negative MPNs but
with an elevation in PAI-1 levels. A significant increase also aid in developing new approaches to personalize the
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in PLT PAI-1 levels was observed in patients with ET with treatment of patients with these diseases.
thrombotic complications compared with patients with ET The JAK2 gene, located on chromosome 9p24.1, encodes
without thrombotic complications. 35 a non-receptor tyrosine kinase involved in cell growth,
PLT PAI-1 plays a pivotal role in the development differentiation, development, and histone modification.
of arterial thrombosis. Arterial thrombi containing Ligand binding to type I or II receptors associated
approximately two to three times more PAI-1 than venous with the JAK2 protein prompts JAK2 to phosphorylate
thrombi are more commonly detected in patients with tyrosine within the cytokine receptor’s cytoplasmic region,
MPNs. In an animal experiment, it was demonstrated thereby generating several docking sites for STAT protein
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that PLT-derived PAI-1 provides a high concentration of recruitment and phosphorylation. Phosphorylated STAT
PAI-1 in arterial thrombi. 37,38 proteins dimerize in the cytoplasm and translocate into the

The quantitative parameters of PLTs, such as nucleus to further activate genes. 7
number, volume, function, and kinetics (production and One of the most prevalent mutations in the JAK2 gene
survival), are genetically determined and depend on the is the V617F, a somatic gain-of-function mutation altering
expression level of many genes. Several genes regulating the 1849 coding nucleotide from guanine to thymine,
th
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PLT quantitative parameters and those governing the resulting in the replacement of valine with phenylalanine.
expression of proteins of the JAK-STAT signaling pathway The JAK2V617F mutation serves as a molecular marker for
and the uPA-uPAR-PAI-1/PAI-2 system are located on MPNs. 7
adjacent chromosomes. In particular, the MPL gene This study demonstrates that the JAK2V617F mutation
(1p34.2) is linked to CSF3R (1p34.3) and JAK1 (1p31.3) was identified in 78.6% of patients diagnosed with MPNs.
genes. The JAK2 gene (9p24.1) is not only located next
to the PLT-associated genes, such as AK3 (9p24.1) and This mutation was observed in 59.1% of patients with
ET, 94.7% of patients with PV, and 86.7% of patients with
RCL1 (9p24.1), but also next to the PGR gene (9p24.1). PMF. This detection rate is consistent with literature data,
The TPM4 gene (19p13.12) is linked to CALR (19p13.13), indicating that the frequency of the JAK2V617F mutation
JAK-3 (19p13.11), and EPOR (19p13.2) genes. It should in patients with ET, PV, and PMF ranges from 31.3 to
be noted that one of the PLT-associated genes, namely 72.1%, 46.7 to 100%, and 25.0 to 85.7%, respectively. 27,44
the FLJ36031-PIK3CG (7q22.3) gene, is located next to
the SERPINE1 gene, which encodes PAI-1, as well as to A body of evidence indicates that the V617F mutation
the EPO gene (7q22.1). This region of chromosome 7 increases the risk of thrombosis and may serve as a predictive
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Volume 3 Issue 2 (2024) 8 doi: 10.36922/gtm.2559