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

1. Introduction coagulation system. An increased number of red blood
cells (RBCs), white blood cells (WBCs), and PLTs, in
Myeloproliferative neoplasms (MPNs) without the conjunction with qualitative abnormalities, contribute to
presence of the Philadelphia chromosome (Ph-negative), a prothrombotic phenotype and a hypercoagulable state.
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commonly referred to as the “classical” MPNs, include This pathogenesis encompasses a range of processes,
essential thrombocythemia (ET), polycythemia vera including aberrant signal transduction, PLT activation,
(PV), and primary myelofibrosis (PMF). These conditions endothelial cell dysfunction, overproduction of tissue
constitute a distinct subgroup of MPNs. In more than 90% factors, formation of PLT-neutrophil aggregates, and
of cases, these conditions are driven by mutations in genes hyperviscosity due to an increase in the RBC mass.
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that regulate the expression of proteins of the Janus kinase– Different gene polymorphisms contribute to these
signal transducer and activator of transcription (JAK- abnormalities. Mutations in JAK2, CALR, and MPL
STAT) signaling pathway. The primary driver mutations activate the JAK/STAT pathway, phosphoinositide-3-
include JAK2V617F, JAK2 exon 12, myeloproliferative kinase/Akt (PI3K/Akt) pathway, and mitogen-activated
leukemia virus oncogene (MPL) W515L/K, and calreticulin protein kinases/extracellular signal-regulated kinase
(CALR). These somatic gene mutations impact cytokine (MAPK/ERK) pathway. In addition, mutations in genes
1,2
signaling, epigenetic regulation, RNA splicing, and signal such as additional sex combs-like 1 (ASXL1) and ten-
transduction to transcription factors, leading to the clonal eleven translocation 2 (TET2) cause epigenetic changes
proliferation of pluripotent hematopoietic stem cells and in DNA and affect the differentiation of hematopoietic
overproduction of cells from various myeloid lineages, cells. These mutations collectively lead to abnormal
which defines the manifestations of Ph-negative MPNs.
proliferation rates in blood cells. 7
The JAK2V617F mutation is the most prevalent The cellular interactions in MPNs create a hyperadhesive
molecular anomaly, identified in over 95% of patients and prothrombotic milieu, predisposing patients to
with PV and 50 – 60% of individuals with ET and PMF. thrombosis. PLTs play a pivotal role in these processes,
3,4
Mutations in the CALR gene, which result in abnormal significantly contributing to thromboinflammatory
interactions with the MPL receptor and subsequent reactions in MPN patients. PLT activation can facilitate
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activation and persistent signaling of the JAK2 pathway, the extrinsic coagulation pathway via an endothelial
5
are observed in 20 – 30% of patients with ET and PMF. P-selectin-dependent mechanism, enhancing their
3,4
Mutations in the MPL gene cause constitutive activation interaction with WBCs, predominantly neutrophils. PLTs
of receptors, leading to excessive platelet (PLT) production bind to leukocytes through activated endothelial cell
and other hematopoietic disorders, and have been observed surface receptors, GPIbα and PSGL-1, thereby mediating
in up to 10% of patients with ET and PMF. Nevertheless, the formation of PLT-leukocyte aggregates. 7
none of the aforementioned mutations are identified in 10
– 25% of patients with ET and PMF. 3,4 It is worth noting that RBCs and PLTs constitute the
majority of both blood cells and human body cells, at
The common features of Ph-negative MPNs include approximately 85% and 4.9%, respectively. This figure
a relatively long and gradual course, development of does not include their precursors in the bone marrow.
9,10
splenomegaly, fibrous changes in the bone marrow, and Consequently, even a minor increase in their absolute
clonal tumor evolution. In addition, these conditions number in the blood circulation results in not only
display an overproduction of red blood cells (RBCs) and hemorheological but also systemic disorders. Unlike
PLTs. Despite these characteristics, the mass of tumor leukocytes, which are transient cells using the bloodstream
5,6
stem cells in MPNs is relatively small. as a communication system to move to various organs and
During the course of Ph-negative MPNs, there is tissues for maturation or function, RBCs and PLTs are
a tendency for the development of thromboembolic stationary blood cells confined to the bloodstream.
complications. Thrombosis has been identified as a The fibrinolytic system plays a key role in thrombolysis
significant contributor to morbidity and mortality in and prevention of fibrosis of the intercellular matrix. The
MPNs, with an estimated prevalence of 20 – 35% in PV urokinase-type plasminogen activator (uPA) system is
patients, 15 – 30% in ET patients, and 10 – 15% in PMF responsible for the activation and regulation of fibrinolysis.
patients. Arterial thrombosis accounts for approximately This system is comprised of uPA, the cellular receptor for
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60 – 70% of all vascular complications. uPA (uPAR), and its inhibitors, plasminogen activator
The pathogenesis of thrombosis in MPNs is inhibitor-1 (PAI-1) and PAI-2 (uPA-uPAR-PAI-1/PAI-
multifactorial, resulting from a complex interaction 2). The uPA system is involved in a number of processes,
between blood cells, the endothelium, and the blood including organ stroma remodeling, angiogenesis,

Volume 3 Issue 2 (2024) 2 doi: 10.36922/gtm.2559