Table 1 Functions and relationship with MPNs of the potential biomarkers of interest for ET patients with CALR and JAK2 mutations

BPI

Bactericidal permeability increasing protein

Encodes for an antimicrobial lipopolysaccharide binding protein stored in the azurophil granules of neutrophils, in the granules of eosinophils and on the surface of monocytes. BPI-expression during myeloid differentiation can be cooperatively and directly mediated by RUNX1, PU.1, and Sp3 [11].

RUNX1 mutations are found in hematological malignancies [12] and the overexpression of RUNX1 has an important role in the development of MPNs [13]. The involvement of the RUNX1 pathway in the leukemic transformation of MPNs also seems to be a common event [14]. PU.1 is a key transcription factor required for myeloid differentiation and the p.V617F JAK2 mutation upregulates its expression in the PB of MPN patients [15]. The transcription factor Sp3 is involved in the regulation of many hematopoietic-specific genes [16]. SP family members are also essential for the transcriptional regulation of CALR [17].

CRISP3

Cysteine-rich secretory protein 8

Encodes for a member of the cysteine-rich secretory protein (CRISP) family within the CRISP, antigen 5 and pathogenesis-related 1 proteins superfamily.

Previously described as upregulated as part of a 7-gene predictive signature of early primary prefibrotic myelofibrosis (prePMF) [18]. It has also been identified as a potential PB biomarker for multiple myeloma [19]. Its role in MPNs remains unclear.

LTF

Lactotransferrin

Encodes for a member of the transferrin protein family that is also found in the secondary granules of neutrophils acting as a potent inhibitor of granulocyte-macrophage colony stimulating factor production when it binds to monocytes and macrophages [22]. This protein is an important component of the non-specific immune system and a major iron-binding protein in milk and body secretions with an antimicrobial activity and a broad spectrum of properties, including regulation of iron homeostasis, host defense against a broad range of microbial infections, anti-inflammatory activity, regulation of cellular growth and differentiation and protection against cancer development and metastasis.

A decrease in the presence [23] and release [24] of lactotransferrin from the neutrophils has been reported in patients with MPNs and may be responsible for an increased myeloid cells proliferation. This gene has been found upregulated in PV, ET and PMF [25].

MMP8

Matrix metalloproteinase 8

Encodes for a member of the matrix metalloproteinase (MMP) protein family involved in the breakdown of extracellular matrix in several processes. MMP8 functions in the degradation of type I, II and III collagens.

Described as upregulated as part of a 7-gene predictive signature of early primary prefibrotic myelofibrosis (prePMF) [18]. Upregulated in PB from patients with PMF and related neoplasms [20] and directly involved in HSC mobilization and trafficking [21].

PBXIP1

PBX homeobox interacting protein 1

Encodes for a protein that inhibits the transcriptional activation potential of PBX1 homeodomain protein (PBX1) by preventing its binding to DNA. This protein can also interact with estrogen receptors alpha and beta, promoting the proliferation of some cancers.

PBX1 regulates the equilibrium between self-renewal and differentiation of HSCs and the stem cell transcriptional program directed by this protein drives tumor progression in MPNs [26].

PTGS1

Prostaglandin-endoperoxide synthase 1

This enzyme catalyzes the conversion of arachidonate to prostaglandin with a dual function as both a cyclooxygenase and as a peroxidase, regulates angiogenesis in endothelial cells and may promote cell proliferation during tumor progression. It is involved in the biosynthesis pathway of prostanoids, in particular in the stomach and platelets.

PTGS1 overexpression has been previously implicated in MPNs [27] and mutations in this gene are associated with bleeding and platelet disfunction [28].