Invited reviewChronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development?
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.
References (100)
- et al.
MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients
Blood
(2006) - et al.
Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression
Blood
(2011) Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?
Blood
(2012)- et al.
Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study
Blood
(2011) - et al.
Inflammation and cancer: back to Virchow?
Lancet
(2001) - et al.
IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer
Cancer Cell
(2009) - et al.
Immunity, inflammation, and cancer
Cell
(2010) - et al.
Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer
Cytokine Growth Factor Rev
(2010) - et al.
Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG islands
Cancer Cell
(2011) Chronic inflammation and mutagenesis
Mutat Res
(2010)
Gene susceptibility to oxidative damage: from single nucleotide polymorphisms to function
Mutat Res
Does oxidative damage contribute to the generation of leukemia?
Leuk Res
The gene encoding thioredoxin-interacting protein (TXNIP) is a frequent virus integration site in virus-induced mouse leukemia and is overexpressed in a subset of AML patients
Leuk Res
Tumor necrosis factor-alpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms
Blood
FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress
Cell
A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche
Blood
The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels
Blood
FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system
Cell Stem Cell
Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells
J Biol Chem
ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage
DNA Repair (Amst)
Foxo3a is essential for maintenance of the hematopoietic stem cell pool
Cell Stem Cell
FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2
Mol Cell
A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders
Mutat Res
Chronic inflammation, mutation and human disease
Mutat Res
Myelofibrosis with myeloid metaplasia: the advanced phase of an untreated disseminated hematological cancer—time to change our therapeutic attitude with early upfront treatment?
Leuk Res
Detection of retrovirus in patients with myeloproliferative disease
Lancet
Human endogenous retrovirus (HERV-K) particles in megakaryocytes cultured from essential thrombocythemia peripheral blood stem cells
Exp Hematol
High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a
Blood
Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera
Blood
Complete hematological, molecular and histological remissions without cytoreductive treatment lasting after pegylated-interferon {alpha}-2a (peg-IFN{alpha}-2a) therapy in polycythemia vera (PV): long term results of a phase 2 trial
Blood (ASH Annual Meeting Abstracts)
The renaissance of interferon therapy for the treatment of myeloid malignancies
Blood
An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation
Cell
Statins in the treatment of polycythaemia vera and allied disorders: an antithrombotic and cytoreductive potential?
Leuk Res
JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders
Blood
Increased in ciculating CD+CD25+Foxp3+ T cells in patients with Philadelphia-negative chronic myelopoliferative neoplasms during treatment with IFN-α
Blood
Mechanisms of disease: the myeloproliferative disorders
N Engl J Med
TET2 mutations in myeloid cancers
N Engl J Med
Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Nat Genet
Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1
Leukemia
Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms
Blood
Identification of genomic aberrations associated with disease transformation by means of high-resolution SNP array analysis in patients with myeloproliferative neoplasm
Am J Hematol
Inflammation and thrombosis in essential thrombocythemia and polycythemia vera: different role of C-reactive protein and pentraxin 3
Haematologica
Pathophysiology of thrombosis in myeloproliferative neoplasms
Haematologica
Increased risk of lymphoid neoplasms in patients with Philadelphia chromosome-negative myeloproliferative neoplasms
Cancer Epidemiol Biomarkers Prev
Tumors: wounds that do not heal, Similarities between tumor stroma generation and wound healing
N Engl J Med
Idiopathic myelofibrosis. Clinical aspects and studies on extracellular matrix metabolism
Dan Med Bull
Inflammation and cancer
Nature
NF-kappaB: linking inflammation and immunity to cancer development and progression
Nat Rev Immunol
Inflammation and cancer: an ancient link with novel potentials
Int J Cancer
Molecular pathways and targets in cancer-related inflammation
Ann Med
Cited by (192)
Risk Factors for Disease Progression and Treatment Goals in Polycythemia Vera
2024, Clinical Advances in Hematology and OncologyClonal hematopoiesis of indeterminate potential: implications for the cardiologists
2024, Journal of Cardiovascular Medicine