Table 3 Functions and relationship with MPNs of the potential biomarkers of interest exclusively for ET patients with JAK2 mutations

ARG1

Arginase 1

Encodes a protein that catalyzes the hydrolysis of arginine to ornithine and urea. Arginine metabolism is a critical regulator of innate and adaptive immune responses.

The myeloid-derived suppressor cells of MPN patients show an increased expression of this protein leading to arginine depletion and suppressor T cell activity [41].

CAST

Calpastatin

Encodes a calpain inhibitor. The calpain/calpastatin system is involved in numerous membrane fusion events, including platelet and erythrocyte aggregation.

This gene has not been directly associated with MPNs but decreased calpastatin expression and elevated calpain activity has been observed in acute myeloid leukemia [42].

CD177

CD177

Encodes a glycosyl-phosphatidylinositol (GPI)-linked cell surface glycoprotein with a role in neutrophil activation. It can bind platelet endothelial cell adhesion molecule-1 and function in neutrophil transmigration.

The overexpression of this gene was proposed as a marker of abnormal neutrophil production in patients with MPNs [43].

CLEC5A

C-type lectin domain containing 5 A

Encodes a member of the C-type lectin/ C-type lectin-like domain (CTL/CTLD) superfamily of proteins critical for myeloid differentiation. Its dysregulation has been associated with myelodysplastic syndromes [25].

DAPP1

Dual adaptor of phosphotyrosine and 3-phosphoinositides 1

Encodes a protein located in plasma membrane predicted to be involved in signal transduction enabling phosphatidylinositol-3,4,5-trisphosphate binding activity and phosphatidylinositol-3,4-bisphosphate binding activity.

Positive regulator of tyrosine kinase-induced cell responses [44] but not related to MPNs until date.

EPS15

Epidermal growth factor receptor pathway substrate 15

Encodes a protein that is part of the EGFR pathway and present at clathrin-coated pits. It is involved in receptor-mediated endocytosis of EGF and may be involved in the regulation of mitogenic signals and control of cell proliferation.

Its fusion with KMT2A has been observed in patients with acute myeloblastic leukemia [45].

IGHM

Immunoglobulin heavy constant mu

Encodes the C-region of the immunoglobulin heavy chain mu, which defines the IgM isotype. Membrane-bound IgM induces the phosphorylation of CD79A and CD79B by the Src family of protein tyrosine kinases and it may cause death of cells by apoptosis.

Not previously associated with MPNs.

IL18RAP

Interleukin 18 receptor accessory protein

Encodes an accessory subunit of the heterodimeric receptor for interleukin 18, a proinflammatory cytokine involved in inducing cell-mediated immunity. It enhances the IL18-binding activity of the IL18 receptor, so it is involved in IL18-dependent signal transduction, leading to NFκB and JNK activation.

Not previously associated with MPNs.

OLFM4

Olfactomedin 4

Encodes a member of the olfactomedin family that is an extracellular matrix glycoprotein that facilitates cell adhesion and promotes tumor growth.

Previously associated with myelofibrosis transformation of ET patients [46] and seems to be a survival factor for primitive leukemia cells [47].

OLR1

Oxidized low density lipoprotein receptor 1

Encodes a low-density lipoprotein receptor that belongs to the C-type lectin superfamily. It internalizes and degrades oxidized low-density lipoprotein and may be involved in the regulation of Fas-induced apoptosis.

This gene is upregulated in patients with chronic myelomonocytic leukemia [48].

RIOK3

RIO kinase 3

Encodes a member of the right open reading frame (RIO) kinase gene family, a serine/threonine kinase with a role in the processing of the pre-40 S ribosomal subunit, 21 S pre-rRNA and in NFκB signaling pathway inhibiting CASP10 isoform 7-mediated activation.

Not previously associated with MPNs.

SELP

Selectin P

Encodes a 140 kDa protein stored in the alpha-granules of platelets that is involved in platelet activation and degranulation, as well as in the interaction of platelets with leukocytes.

Vascular endothelial expression of the p.V617F mutation in JAK2 has been described to increase the expression of SELP promoting a pro-thrombotic state [49].

THBS1

Thrombospondin 1

Encodes a subunit of a disulfide-linked homotrimeric protein, an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein can bind to fibrinogen, fibronectin, laminin, type V collagen and integrins alpha-V/beta-1 with roles in platelet aggregation, angiogenesis, and tumorigenesis.

THBS1 is overexpressed in PV and ET patients [50] and PMF megakaryocytes secrete this protein leading to angiogenesis and myelofibrosis development [51].