Review on PF4V1 (Platelet Factor 4 Variant 1), with data on DNA, on the protein encoded, and where the gene is implicated

Proost, P

Struyf, S

Van, Damme J

Van, Raemdonck K

Atlas of Genetics and Cytogenetics in Oncology and Haematology

I-Revues

  
 
 
   
Gene Section 
Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(3) 198 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology 
INIST-CNRS 
 
OPEN ACCESS JOURNAL 
PF4V1 (platelet factor 4 variant 1) 
Katrien Van Raemdonck, Paul Proost, Jo Van Damme, Sofie Struyf 
Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of 
Microbiology and Immunology, KU Leuven, Leuven, Belgium (KVR, PP, JVD, SS) 
 
Published in Atlas Database: June 2014 
Online updated version : http://AtlasGeneticsOncology.org/Genes/PF4V1ID44606ch4q13.html 
DOI: 10.4267/2042/56412 
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 
© 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Abstract 
Review on PF4V1, with data on DNA/RNA, on the 
protein encoded and where the gene is implicated. 
Identity 
Other names: CXCL4L1, CXCL4V1, PF4-ALT, 
PF4A, SCYB4V1 
HGNC (Hugo): PF4V1 
Location: 4q13.3 
Note 
The CXC chemokine CXCL4L1 is a nonallelic 
variant of the earlier identified platelet factor 
CXCL4. These rather atypical chemokines display 
a less prominent leukocyte chemoattractant activity, 
yet influence a large range of other processes. 
CXCL4L1 was characterized as an especially 
potent angiostatic chemokine (Struyf et al., 2004). 
Consequently, this platelet factor is an inhibitor of 
tumor growth and metastasis. The therapeutic 
potential of CXCL4L1 has been evidenced in 
preclinical B16 melanoma, Lewis lung carcinoma 
and A549 adenocarcinoma animal models, as it 
inhibited both tumor growth and metastasis by 
preventing tumor neovascularization (Struyf et al., 
2007). Furthermore, the carboxy-terminal peptide 
CXCL4L147-70 retains its potential to suppress B16 
melanoma growth in mice (Vandercappellen et al., 
2010). Additionally, the recently highlighted impact 
of CXCL4L1 on lymphatic endothelial cells in 
vitro, corroborates a potential inhibitory effect on 
tumor dissemination in vivo (Prats et al., 2013; Van 
Raemdonck et al., 2014). Compared to CXCL4, the  
affinity of CXCL4L1 for glycosaminoglycans 
(GAG) is rather moderate (Dubrac et al., 2010; 
Struyf et al., 2011), strongly increasing its in vivo 
half-life and diffusibility. 
DNA/RNA 
Note 
The gene and mRNA for CXCL4L1 are 1293 and 
741 bp in length, respectively. 
Description 
The CXCL4L1 mRNA is encoded by three exons. 
Duplication of the CXCL4 gene, giving rise to the 
homologous CXCL4L1 gene, is conserved in 
human and other primates including gorilla, 
chimpanzee, orangutan, gibbon and macaque. 
Transcription 
The existence of a CXCL4 variant was first 
evidenced by Eisman et al. (1990) and Green et al. 
(Eisman et al., 1990; Green et al., 1989). The 
CXCL4L1 mRNA is predominantly present in 
platelets, but has also been detected in vascular 
smooth muscle cells and to a lesser extent in T 
cells, monocytes and endothelial cells (Lasagni et 
al., 2007). CXCL4L1 mRNA detected in ovarian 
tissue has been attributed to macrophage CXCL4L1 
expression (Furuya et al., 2012). CXCL4L1 
expression was also observed in the HCT-8 colon 
adenocarcinoma cell line as evidenced by qPCR 
analysis (Verbeke et al., 2010). 
Pseudogene 
None. 
PF4V1 (platelet factor 4 variant 1) Van Raemdonck K, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(3) 199 
 
Figure 1. Structure of the human CXCL4L1 gene. This figure schematically depicts the structure of the human CXCL4L1 gene 
as described in the NCBI database (NM_002620). Lines represent the introns, whereas rectangular exons are coloured blue, 
yellow and green to represent the non-coding domains, the signal peptide and the mature protein, respectively. Grey numbers 
indicate the basepairs (bp) spanning the exons. Red numbers apply to the amino acids (aa) encoded. 
 
Protein 
Note 
CXCL4L1 precursor: 104 amino acids (aa), 11553 
Da; CXCL4L1 mature: 70 aa, 7805.8 Da. 
Description 
CXCL4L1 is a member of the CXC chemokine 
family of chemoattractant cytokines.  
CXCL4L1 is a non-ELR CXC chemokine, meaning 
that it lacks the sequence glutamic acid-leucine-
arginine just in front of the two NH2-terminally 
located conserved cysteine residues. 
Expression 
Blood platelets release both CXCL4 and CXCL4L1 
after activation.  
The exact location of CXCL4L1 inside the platelet 
is not yet determined, whereas platelet CXCL4 is 
stored in the alpha-granules.  
In other cell types as well, CXCL4 is stored in 
secretory granules and released in response to 
protein kinase C activation, whereas CXCL4L1 is 
continuously synthesized and secreted through a 
constitutive pathway (Lasagni et al., 2007).  
For instance, human aortic smooth muscle cells and 
human coronary smooth muscle cells constitutively 
release CXCL4L1.  
Specific cancer cell lines have also been shown to 
produce CXCL4L1.  
Secretion of CXCL4L1 in tumoral tissue was 
evidenced in vitro on stimulated osteosarcoma cells 
through the use of ELISA and further corroborated 
by immunohistochemical staining of different 
human sarcoma tissue sections (osteosarcoma, 
leiomyosarcoma and liposarcoma) 
(Vandercappellen et al., 2007).  
Furthermore, CXCL4L1 was strongly detected in 
colorectal adenocarcinoma biopsy specimens 
(Verbeke et al., 2010). 
Localisation 
Secreted. 
Function 
CXCL4L1 has been described to be a strong 
inhibitor of angiogenesis. Together with its 
potential to chemoattract T cells, natural killer cells 
and immature dendritic cells, the vascular effects 
contribute to the antitumoral action of CXCL4L1 
(Struyf et al., 2011). Struyf et al. (Struyf et al., 
2007) indeed indicated the angiostatic platelet 
factor to exert an antitumoral effect by inhibiting 
branching of the vascular network and metastasis. 
Considering neutrophils and monocytes, CXCL4L1 
as opposed to CXCL4 would not attract these pro-
tumoral phagocytes (Vandercappellen et al., 2007).  
Lasagni et al. identified a splice variant of CXCR3, 
which was named CXCR3B, as a functional GPCR 
for CXCL4 (Lasagni et al., 2003). Currently, both 
CXCL4 and CXCL4L1 are known to activate 
CXCR3A, as well as CXCR3B (Mueller et al., 
2008; Struyf et al., 2011; Van Raemdonck et al., 
2014). In general, proliferative and positive 
migratory effects are supposed to be mediated by 
CXCR3A, whereas inhibition of chemotaxis, anti-
proliferative and apoptotic effects are postulated to 
be provoked via CXCR3B (Lasagni et al., 2003). 
Besides endothelial cells and T cells, CXCR3 
expressing cell types can be extended to fibroblasts, 
mesangial cells, airway epithelial and smooth 
muscle cells, pneumocytes and several sarcoma, 
carcinoma and myeloma cell types (Billottet et al., 
2013).  
CXCL4 exerts its action through many different 
mechanisms, including binding to GAG and 
heteromultimerisation with other chemokines and 
growth factors, whereas in the case of CXCL4L1 its 
distorted structure and unique protruding C-
terminal helix are assumed to conflict with this 
mode of action. The open formation characteristic 
of CXCL4L1 decreases GAG-binding, however 
simultaneously enhancing anti-angiogenic and anti-
tumoral effects (Dubrac et al., 2010; Kuo et al., 
2013). Additionally, CXCL4L1 forms more stable 
homodimers due to a loss in positive charge.  
PF4V1 (platelet factor 4 variant 1) Van Raemdonck K, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(3) 200 
This gained stability is likely to interfere with the 
ability to form heteromers which requires initial 
dissociation of the homomultimers (Kuo et al., 
2013). 
Homology 
CXCL4L1 is a non-allelic variant of CXCL4. 
Unlike CXCL4, its variant appears only in 
primates. In men, mature proteins only differ in 3 
amino acids. On the other hand, the signal peptide 
of human CXCL4L1 displays 38% amino acid 
divergence compared to human CXCL4, affecting 
its subcellular localization and regulated secretion 
mechanism, as was described by Lasagni et al. 
(Lasagni et al., 2007). 
Implicated in 
Osteosarcoma 
Disease 
Secretion of CXCL4L1 in tumoral tissue was 
evidenced in vitro on stimulated osteosarcoma cells 
through the use of ELISA and further corroborated 
by immunohistochemical staining of different 
human sarcoma tissue sections (osteosarcoma, 
leiomyosarcoma and liposarcoma) 
(Vandercappellen et al., 2007). On the other hand, 
osteosarcoma cells also express the CXCR3 
receptor guiding initial tumor dissemination to 
metastatic sites were CXCR3 ligands such as 
CXCL4L1 are expressed (Pradelli et al., 2009). 
Colorectal cancer 
Disease 
Study of CXCL4L1 expression in human epithelial 
tumors revealed a distinct presence of CXCL4L1 in 
colorectal cancer cells, whereas its expression in 
esophageal cancer was weak to undetectable 
(Verbeke et al., 2010). ELISA, qRT-PCR, 
immunocytochemistry as well as ex vivo 
immunohistochemistry support the hypothesis that 
CXCL4L1 is secreted by colorectal 
adenocarcinoma cells and may affect the complex 
process of tumor development. However, no 
correlation was found between the intensity or 
extent of CXCL4L1 staining of patient biopsies and 
the TNM stage. On the other hand, intratumorally 
administered CXCL4L1 has been shown to reduce 
tumor vascularization and, consequently, tumor 
growth and metastasis of A549 adenocarcinoma in 
mice, similar to its therapeutic benefit observed in 
preclinical studies on B16 melanoma and Lewis 
lung carcinoma (Struyf et al., 2007). 
Endometriosis-associated ovarian 
cancer (EAOC) 
Oncogenesis 
Both clear cell and endometrioid types of ovarian 
cancers occasionally develop on the bases of 
endometriosis. CXCL4L1 is expressed in normal 
ovaries and especially during endometriosis 
(Furuya et al., 2012). However, CXCL4L1 mRNA 
levels were significantly lower in cancerous lesions. 
Endometriosis-associated ovarian cancers (EAOC) 
were reported to be infiltrated by CD68+ tumor-
associated macrophages. CXCL4 and CXCL4L1 
expression by those macrophages was studied at the 
protein level by Furuya and colleagues. However, 
antibodies not distinguishing CXCL4 from its 
variant were used. The tumor-associated 
macrophages displayed an impaired expression of 
either CXCL4, CXCL4L1 or possibly both. In 
conclusion, macrophage expression of the platelet 
factors appears to be associated with EAOC disease 
state and may prove to be a useful disease marker. 
Coronary artery disease 
Prognosis 
Recently, a possible prognostic significance for 
CXCL4L1 was evaluated in patients suffering from 
coronary artery disease (CAD) (De Sutter et al., 
2012). Specifically in a selection of patients with 
stable CAD and preserved left ventricular function, 
CXCL4L1 levels significantly correlated to age, 
creatinine and circulating platelet number, as well 
as to N-terminal pro-B-type natriuretic peptide 
(NT-proBNP), a well validated prognostic marker 
in stable CAD. More importantly, CXCL4L1 
showed an additional prognostic value on top of 
NT-proBNP as lower levels of CXCL4L1 predicted 
a higher event rate and worse outcome. 
Surprisingly, in these patients with stable CAD the 
prognostic value of CXCL4L1 is independent of 
NT-proBNP. 
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This article should be referenced as such: 
Van Raemdonck K, Proost P, Van Damme J, Struyf S. 
PF4V1 (platelet factor 4 variant 1). Atlas Genet Cytogenet 
Oncol Haematol. 2015; 19(3):198-201. 


PF4V1 (Platelet Factor 4 Variant 1)

Raemdonck K Van

P Proost

Damme J Van

S Struyf

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PF4V1 (Platelet Factor 4 Variant 1)

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