Elsevier

Leukemia Research

Volume 37, Issue 2, February 2013, Pages 214-220
Leukemia Research

Invited review
Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development?

https://doi.org/10.1016/j.leukres.2012.10.020Get rights and content

Abstract

The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms, in which a stem cell lesion induces an autonomous proliferative advantage. In addition to the JAK2V617 mutation several other mutations have been described. Recently chronic inflammation has been proposed as a trigger and driver of clonal evolution in MPNs. Herein, it is hypothesized that sustained inflammation may elicit the stem cell insult by inducing a state of chronic oxidative stress with elevated levels of reactive oxygen species (ROS) in the bone marrow, thereby creating a high-risk microenvironment for induction of mutations due to the persistent inflammation-induced oxidative damage to DNA in hematopoietic cells. Alterations in the epigenome induced by the chronic inflammatory drive may likely elicit a “epigenetic switch” promoting persistent inflammation. The perspectives of chronic inflammation as the driver of mutagenesis in MPNs are discussed, including early intervention with interferon-alpha2 and potent anti-inflammatory agents (e.g. JAK1-2 inhibitors, histone deacetylase inhibitors, DNA-hypomethylators and statins) to disrupt the self-perpetuating chronic inflammation state and accordingly eliminating a potential trigger of clonal evolution and disease progression with myelofibrotic and leukemic transformation.

Introduction

The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) – essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) – are clonal stem cell diseases, which arise due to an acquired genetic defect in the pluripotent stem cell. The nature of this initiating genetic defect remains to be established. Several “second hit” genetic aberrations have been identified giving rise to dysregulation of various signaling pathways, which control blood cell production. One of these is the JAK2V617 mutation, which is present in virtually all patients with PV and in half those with ET and PMF [1]. According to “The Biological Continuum” concept these neoplasms evolve from an early disease stage (ET) to the advanced myelofibrosis stage, implying in the JAK2V617-positive patients a steady increase in the JAK2V617F mutational load from “low burden” JAK2V617F-positive ET over PV to the advanced burnt-out myelofibrosis stage. According to this model, the JAK2V617F-positive PMF patient likely has been hit by the “primary lesion” several years ago (10–20 years), resulting in elevated platelet counts only or slightly elevated leukocyte and platelet counts – an “ET-phenotype” – but the disease has slowly evolved without giving rise to clinical symptoms before being diagnosed with PMF or the patient has accustomed to disease-related symptoms (e.g. fatigue and other hypermetabolic symptoms). Other genetic “second hit lesions” have been identified, including mutations in the MPL, TET2, EZH2, ASXL1, LNK, and CBL genes, contributing to unregulated Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling, modulation of transcription, and accumulation of oncoproteins. However, it is unknown how all these abnormalities interact and influence disease evolution from early stage disease to the advanced burnt-out myelofibrosis stage and terminal blast crisis (myelofibrotic and leukemic transformation) [2], [3], [4], [5], [6], [7], [8].

The MPNs are associated with a chronic inflammatory state due to the continuous release of inflammation products from in vivo activated leukocytes and platelets [9], [10], [11]. In fact, in this context the MPNs might be considered and described as a “Human Inflammation Model”, illustrating the devastating consequences of chronic inflammation in MPNs – premature atherosclerosis, immune deregulation with loss of tumor immune surveillance, clonal evolution with myelofibrotic and leukemic transformation and an increased risk of second cancer as well [11], [12], [13].

Chronic inflammation is characterized by persistently activated immune cells, DNA damage, tissue destruction, remodeling and fibrosis, which in MPNs is exemplified by the myelofibrosis stage – the terminal phase of MPNs and the consequence of chronic inflammation in the bone marrow – “the inflamed bone marrow” – “the wound that won’t heal” [14], [15]. Accordingly, chronic inflammation is strongly associated with the development of human cancers and today a causal link between chronic inflammation and cancer is well accepted [16], [17], [18], [19], [20].

As in other chronic inflammatory conditions chronic inflammation in the bone marrow likely is associated with increased NF-kappa-beta (NF-κB) activity in hematopoietic cells and stroma cells, exposing these cells to a constant oxidative stress [18]. Furthermore, increased NF-κB is also associated with increased production of TNF-alpha and IL-6, which by itself can increase NF-κB and STAT3 with ensuing inhibition of apoptosis and increased myeloproliferation – all events providing an environment conductive to malignant transformation and expansion. Importantly, chronic inflammation is also associated with an increase in DNA methylation with a continuous increase during tumor development [21]. Several studies in MPNs have shown aberrant DNA methylation patterns being most pronounced in patients with advanced disease (myelofibrosis), in which hypermethylation of the CXCR4 promoter and the SOCS3 promoter [22], [23] have been reported, but not in patients with ET and PV [23], [24], [25]. Accordingly, it is tempting to speculate, if chronic inflammation may have a major impact upon DNA-methylation in MPNs, exposure to the mediators of inflammation further promoting aberrant DNA methylation patterns to be conductive to tumor development.

Considering the increasing number of mutations – in signaling pathways (JAK2V617F, MPL, LNK) and in gene transcription pathways (TET2, ASXL1, IDH1/2) – being identified in patients with MPNs [2], [3], [4], [5], [6], [7], [8] a link between chronic inflammation and induction of some of these mutations in MPNs is worthy of consideration. Herein, it is hypothesized that a chronic inflammatory bone marrow microenvironment may result in epigenetic changes, genomic instability and DNA mutations in hematopoietic cells, which accordingly both may initiate clonal development (initial hit in the hematopoietic stem cells) but also driving clonal evolution by triggering additional mutations (second hits) and accordingly further enhancing clonal expansion and release of inflammatory products.

Section snippets

The link between chronic inflammation, mutagenesis and cancer

Chronic inflammation is associated with an increase in cytokines, chemokines and reactive oxygen and nitrogen species, altogether giving rise to epigenetic changes, genomic instability and DNA mutations, which thereby contribute to tumor initiation [26], [27], [28], [29], [30]. Furthermore, inflammation also drives tumor progression and metastasis via additional genetic changes. During this process, the close interaction between cancer cells, immune cells and stromal elements and the factors

Chronic inflammation and activated molecular pathways

Inflammatory mediators activate oncogenic transcription factors such as NF-κB and STAT3, which both play major roles in linking inflammation and carcinogenesis. The transcription factor NF-κB is triggered in response to infectious agents and pro-inflammatory cytokines, implying altered expression of several genes, which ultimately provides an environment, having the potential to promote tumorigenesis, if an immune response is sustained [32].

STAT3 is induced by several cytokines, including IL-6

Chronic inflammation and the epigenome

Epigenetic alterations are recorded during inflammation and inflammation-associated carcinogenesis as typically seen in ulcerative colitis [21], [37], [38]. Important mediators of these inflammation-induced DNA methylation changes are oxidative stress and increased pro-inflammatory cytokines, including IL-6, IL-1b, and TNF-alpha [21], [39], [40], [41]. The mechanism(s) how these factors alter the DNA methylation pattern during inflammation is still not completely understood. However, since

Chronic inflammation and mutations in human diseases

As noted above chronic inflammation is associated with oxidative damage to DNA, implying a risk of mutations and ultimately development of cancer [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [42], [43], [44]. A prerequisite in the defence against clonal evolution and cancer development during chronic inflammation is an effective DNA repair mechanism of the sustained oxidative stress induced by the chronic inflammatory drive. Accordingly, mutations in DNA repair mechanisms

The MPNs as a “Human Inflammation Model”

Most recently the potential link between chronic inflammation and the development of myeloproliferative cancer has been described [11]. It was hypothesized, that chronic inflammation might be both a trigger and a driver of clonal evolution, accelerated atherosclerosis and second cancer [11]. Indeed, the MPNs may be considered as a “Human Inflammation Model”, since the disease per se elicits a state of chronic inflammation due to the continuous release of inflammatory products from in vivo

The inflamed stem cell niche

The MPNs are acquired stem cell neoplasms arising due to a yet unidentified stem cell lesion [1]. Herein, it is hypothesized that the initiating event for this acquired stem cell lesion might be consequent to a chronic sustained inflammation stimulus with an ensuing chronic long-lasting myelopoietic drive, ultimately eliciting a genetic stem cell insult. When this event occurs the clone per se continuously generates inflammatory products in the bone marrow. These products – e.g. tumor necrosis

The inflamed circulation

Patients with MPNs are exposed to a sustained risk of thrombosis consequent to increased cell counts and in vivo leukocyte, platelet and endothelial activation, elicited by clonal myeloproliferation per se but also by chronic inflammation mediated by inflammatory products, which continuously are being released from activated leukocytes and platelets [9], [10], [11]. Accordingly, it has been argued that chronic inflammation in MPNs may trigger and drive early development of atherosclerosis akin

JAK2 overexpression and genomic instability

Chronic inflammation is associated with JAK-STAT activation and JAK2 overexpression [51]. Recent studies have shown, that not only the JAK2V617F mutation but also sustained JAK2-overexspression may induce genomic instability and thereby a risk of mutagenesis, which may be of crucial importance in the context of a link between chronic inflammation and the complexity of mutations in MPNs with a steady increase in their frequencies from early disease stage to the advanced myelofibrosis stage. In

Is chronic virus infection the link between chronic inflammation, epigenomic deregulation, genomic instability, mutagenesis and clonal evolution in MPNs?

Several years ago endogenous retrovirus (HERV-K) particles were reported in megakaryocytes cultured from patients with ET [73], [74]. Accordingly, in the context of chronic inflammation as a potential trigger and driver of clonal evolution [11] it is indeed intriguing to consider, if the marked deregulation of inflammation and immune genes [75], [76], [77], many of these having been reported to be deregulated in virus-induced malignancies, might be consequent to a chronic inflammatory state

Discussion and perspectives

Chronic inflammation has most recently been suggested as a potential trigger and driver of clonal evolution, premature atherosclerosis and second cancer in patients with MPNs [11]. Since the identification of the JAK2V617 mutation in 2005 several other mutations in increasing numbers have been reported in MPNs – both in signaling pathways (MPL, LNK in addition to JAK2V617) and in gene transcription pathways (TET2, ASXL1, IDH1/2) as well [2], [3], [4], [5], [6], [7], [8].

Taking into account that

Funding source

None.

Conflict of interest statement

The author has no conflict of interest to declare.

Acknowledgement

None.

Contributions. H.C.H. wrote and edited the manuscript.

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