Page 47 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE - CXCL8 in primary myelofibrosis
G. Vermeersch et al.
While in the past they were considered as separate entities, it is currently well accepted that MPN form a continuum wherein entities can evolve into each other. However, the exact mechanisms of disease development, transforma- tion, and progression remain to be elucidated. MPN may be considered to be a model of inflammation-related can- cer development as each MPN entity is characterized by sustained activation of various immune cells and tends to show a unique cytokine expression pattern within BM and peripheral blood (PB). Expression of the pro-inflammatory chemokine CXCL8 (also known as interleukin-8 [IL-8]) is increased in PB and BM plasma of patients with myelo- fibrosis and its concentration negatively correlates with overall survival (OS).4-6 Here we discuss the potential role of CXCL8 and its cognate receptors CXCR1/2 in the patho- genesis of PMF.
Mutational architecture within primary myelofibrosis: the role of key driver and additional mutations
As mentioned above, the JAK2, CALR and MPL genes fre- quently carry acquired MPN-restricted driver mutations. The JAK2 protein is a member of the JAK family and is charac- terized by two kinase domains amongst which one is cata- lytically active while the other functions as a pseudokinase preventing self-activation. JAK2 is intracellularly connected with receptors such as the erythropoietin receptor (EPOR), MPL, and granulocyte-colony stimulating factor receptor (G-CSFR). Activation by the appropriate ligands induces a conformational change and then results in activation of JAK2 through phosphorylation. Phosphorylated JAK2 functions as a docking station for signaling molecules, such as sig- nal transducer and activator of transcription (STAT), which eventually initiates further downstream signaling resulting in cellular proliferation.7 Independently from STAT, JAK2 may also initiate other signaling pathways, e.g., mitogen activated protein-kinase (MAPK), AKT (protein kinase B) or phosphoinositide 3 (PI3)-kinase (Figure 1).
The MPL gene codes for the thrombopoietin (TPO) recep- tor, which activates JAK2 upon binding of its ligand. Within MPN, gain-of-function-mutations of MPL typically occur at amino acid W515 causing activation of the MPL receptor, and downstream JAK-STAT signaling, independently from TPO binding.5-7
In contrast to the genes mentioned above, the CALR en- coded protein is not directly involved in cellular prolifer- ation but is a chaperone contributing to calcium storage and structural control of N-glycosylated proteins. In its mutated form, CALR interacts with the TPO receptor and induces constitutive activation of JAK2 and STAT proteins without binding of TPO. CALR mutations are described as type 1 or 2 depending on the presence of a 52-base pair
deletion or 5-base pair insertion in exon 9, respectively.7-9 Type 1, which is more prevalent in PMF, is associated with greater phenotypic changes, including BM hypocellularity and megakaryocytic lineage amplification.10
Instead of being monoclonal, MPN may possibly be an oli- goclonal disease characterized by the existence of several molecular distinct clones at once. Previously it has been proposed that patients with MPN may generally show two distinct patterns of acquiring mutations. Firstly, those who acquire mutations in a driver gene followed by additional mutations. Secondly, those acquiring driver mutations on a background of mutations already present in non-driver genes. Many of these affected non-driver genes, such as Tet methylcytosine dioxygenase 2 (TET2) and DNA methyltrans- ferase 3 (DNMT3A), are frequently involved in the age-re- lated phenomenon clonal hematopoiesis of intermediate potential (CHIP). CHIP is characterized by the acquisition of somatic mutations resulting in the expansion of clonal hematopoietic progenitor cells. Several genes predict worse prognosis or are associated with blast phase when mutat- ed; amongst these are TET2, ASXL1, and TP53.11,12 The role of inherited variants in these genes is still not completely understood and concerns a growing area of research within MPN.11 Germline polymorphisms may contribute or predis- pose a person to the development of a chronic inflamma- tory state, characterized by increased cytokine production or myeloid response, and thus genetic instability or even MPN development.5,11
Megakaryocytes in primary myelofibrosis
In recent years, researchers studying MPN pathophysiology expanded their focus from hematopoietic stem and progeni- tor cells (HSPC) to the whole microenvironment surrounding these cells, called ‘the bone marrow niche’.5 The BM is one of the most complex tissues within the human body and comprises multiple cell types, such as endothelial cells, multipotent mesenchymal stromal cells, osteoblasts, and adipocytes. As such, one cell type may influence the func- tioning of another and vice versa. It is well known that the composition and functioning of the BM niche is extensively influenced by changing conditions, such as inflammation or infection.13-15 Megakaryocytes play a central role within MPN pathogenesis. The mutually exclusive driver mutations mentioned above result in constitutive activation of the JAK2 signaling pathway, which initially results in mega- karyocyte hyperplasia and subsequently dysplasia.7 Aber- rant megakaryopoiesis is a pathological hallmark of MPN, as megakaryocytes in myelofibrosis display morphologic abnormalities such as hypolobulated nuclei and clustering. Next to this, higher proliferative capacities and decreased rates of apoptosis are observed. Single cell analysis revealed aberrant molecular signatures and differentiational bias
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