Classical/Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are a group of hematologic malignancies including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Each subset (PV, ET, PMF) has its unique clinical features with a unifying theme of somatic acquisition of a mutation in either Janus Activated Kinase 2 (JAK2^V617F ) (1–5), Calreticulin (CALR) (6, 7) or Thrombopoietin Receptor (TPOR, MPL) in a Hematopoietic Stem Cell (HSC). JAK2^V617F mutations can be seen in all three subtypes of MPN, whereas CALR or MPL mutations are restricted to ET and PMF. This change leads to an overproduction of any combination of white cells, red cells, and platelets, with major clinical consequences including increased risk of thrombosis, and constitutional symptoms. Development of MF, primary (PMF) or secondary to PV/ET, results in cytopenias and risk of transformation to acute leukemia. Chronic inflammation is a hallmark feature of MPN, most notably PMF, which plays an integral role in multiple aspects of its pathobiology, including symptomatology, thrombosis, disease progression, and heightened cardiovascular disease risk (8–11). Although MPN is currently classified as a malignancy, many of the aspects of the disease are more like a chronic inflammatory condition rather than a cancer.

In the sections below, we will highlight specific clinical and pathobiological overlaps between inflammatory disease and each subset of MPN, summarized in Figure 1.

The identification of somatic mutations leading to expansion of a clone transitioned the nomenclature of ET, PV, and PMF from a disorder to a neoplasm. However, presence of a clone with an MPN driver mutation can be seen in humans without a clinical MPN. JAK2^V617F is the 5^th most common mutation seen in clonal hematopoiesis of indeterminate potential (CHIP) (47). Screening of almost 20,000 Danish citizens revealed presence of somatic JAK2^V617F and CALR mutations in 3.2 and 0.16 percent of the population (48). Screening of >250,000 people who have submitted samples to 23andme personal genome service who denied a history of MPN revealed JAK2^V617F in approximately 0.2% of these samples (49).

The clonal architecture of MPN can be complex, with additional mutations acquired in the MPN clone either before or after the MPN driver mutation, or in separate clones from the MPN driver clone (50, 51). Mutations in high risk genes including ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation (52). Patients with an ASXL1 mutation on its own had no increased prognostic to a worsening outcoming, unless when compounded with one of the high-risk genes (53).

A perceived distinguishing factor between hematologic malignancy and inflammatory disease is somatic mutations, present in hematologic malignancy but absent in autoimmune/inflammatory disorders. However, this line is also blurring. Somatic mutations in hematopoietic cells are being identified in inflammatory conditions. A prime example of somatic mutations of myeloid lineage cells causing a severe inflammatory disorder is VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (54). VEXAS is caused by somatic mutations in UBA1 that result in systemic inflammation and progressive bone marrow failure that presents late in life.

Patients with other non-malignant autoimmune disorders harbor somatic mutations in T cells. Individuals with newly diagnosed, untreated Rheumatoid Arthritis (RA) are found to harbor somatic mutations in clonally expanded CD8+ T cells (55). Somatic mutations in the CD8+ T cell compartment have also been identified in patients with myasthenia gravis (56).

There is a significant overlap in the autoimmune disease and MPN patient populations. A prior history of any autoimmune disease was found to be associated with a significantly increased risk of MPN with an Odd’s Ratio (OR) of 1.2 (57). Another study found a significantly increased risk of MPNs in subjects with a prior history of any autoimmune disease (OR=1.86) (58). MPN is likely underappreciated in patients with autoimmune disease, as elevated platelets could be attributed to reactive thrombocytosis in this patient population. Analysis of patients with thrombocytosis (platelets > 450) in an inflammatory bowel clinic revealed that 23% of them harbored JAK2^V617F mutations (59).

It is important to distinguish the myeloproliferative neoplasm PMF from autoimmune MF (AIMF). While both conditions cause fibrosis, cytopenia, and elevated inflammatory cytokines, AIMF will present with serological evidence of autoantibodies and lack of MPN driver mutations (60). However, PMF patients may contain autoantibodies, especially from a prior autoimmune disease, requiring a physician to not rely on this test alone (61).

For various auto-immune conditions, a high degree of heritability is seen among family members of the affected patient, especially in first-degree relatives (62, 63). This can be due to several conditions centered around similar genetic makeup and environmental exposures. There is also a familial predisposition to acquire MPN. A study involving 35,037 hematologic malignancies patients and 93,199 of their first degree relatives found an increased risk of developing AML (RR 1.53), MDS (RR 6.87), and the MPN subtypes PV (RR 7.66) and ET (RR 6.3) if a family member has the disease (64). A search for the genetic basis of the predisposition to acquire MPN has revealed single nucleotide polymorphisms (SNPs) associated with MPN, for example the germline haplotype (GGCC, referred to as “46/1”) encompassing the 3’ region of the JAK2 gene is associated with a three- to four-fold risk of MPN (65). Interestingly, this same JAK2 46/1 haplotype also increases susceptibility to Crohn’s disease, an autoimmune inflammatory bowel disease (66). However, the genetic predisposition to acquire MPN has yet to be fully elucidated.

A common activator of the disease state in MPN and autoimmune disease may be exposure to a severe inflammatory stimulus such as infection. An emerging theme among mutations associated with myeloid malignancies and clonal hematopoiesis of indeterminate potential is resistance to chronic inflammation. For example, many chronic inflammatory stimuli, including Interferon-gamma (IFN-γ (67) and TNF-alpha (TNFα) (45, 68) augment the selective advantage of clones with myeloid malignancy associated mutations in mouse models. However, the impact of an acute inflammatory stressors on the emergence of neoplastic clones is an area less studied. An acute inflammatory stimulus may allow for the expansion of a neoplastic clone to reach a critical threshold after which chronic low grade inflammation, either from environmental sources or driven by the neoplastic clone itself maintains the selective pressure in favor of continued expansion of the clone. Further research, both epidemiologic and mechanistic is required to elucidate the impact of acute infectious stressors on the development of MPN.

Epidemiologic data support the notion that infection may promote development of MPN. A large Swedish population-based study demonstrated that a history of infection was associated with an increased risk of AML and MDS (69). Using the Surveillance, Epidemiology and End Result (SEER)-Medicare database Titmarsh et al. found that MPN was significantly associated with a history of cellulitis (70). Infection is a well-established trigger for autoimmune disease. There are different mechanisms by which an infection may trigger autoimmunity, including molecular mimicry, epitope spreading, and bystander activation. Exposures to specific pathogens have been associated with specific autoimmune disease. Increased amounts of antibodies formed against various bacteria have been linked to driving lupus (71). Epstein-Barr virus infection have been implicated in the pathogenesis of multiple sclerosis (72).

The most notable therapy overlap is the use of JAK inhibitors as a mainstay of treatment in both MPN and autoimmune disease. While in MPN, JAK inhibitors suppress constitutively active JAK/STAT signaling, their ability to reduce inflammation in general may be their broader mechanism of action. The JAK inhibitor ruxolitinib reduces inflammation, however not down to the level of normal (36). This suggests that additional anti-inflammatory drugs, such as those that target the NF-ĸB pathway could work synergistically with JAK inhibitors to quell inflammation in MPN. Prior to the JAK inhibitor era, anti-TNF agents had been investigated in MPN (73), however not nearly to the depth as anti-TNF agents in autoimmune disease. This highlights the common goal in MPN and CID therapy is to reduce inflammation. Further treatment that addresses anti-inflammation specifically (in combination with JAK inhibitors) is being studied, specifically the targeting of TNF-α receptors 1/2 (TNFR1/2) to help control constitutive symptoms (74).

Interferon-alpha (IFNα) is used in MPN in multiple formulations and has the potential of inducing a molecular response (75–77). IFNα can exacerbate autoimmune conditions (78), demonstrating that some drugs used for MPN may be contraindicated in autoimmune disease. However, other interferons are used for autoimmune disease. Evidence supports an anti-inflammatory and beneficial role of IFNβ locally in the joints of patients with rheumatoid arthritis and in murine arthritis models, and many patients with multiple sclerosis show a clinical response to recombinant IFNβ (79).

Interventions such as physical activity and yoga have been implicated in reduction of symptom burden and improvement in quality of life in MPN (80–82). A role between increased inflammation and development of depression has been characterized in recent years, encouraging the development of depression reduction techniques (83, 84). Pilot studies with the mindfulness meditation app Calm suggest that this may be effective in reducing depression and anxiety symptoms in MPN patients (85–87). A randomized online yoga intervention demonstrated small effects on sleep, pain, and anxiety as well as a moderate effect on depression (80). Ultimately, a multimodal lifestyle approach (diet, exercise, mindfulness) is likely the optimal intervention in MPN, but first we must rigorously interrogate the impact of each modality on its own before combining them into a holistic lifestyle approach to improving health in MPN.

Dietary management may represent a low-risk way to optimize cardiovascular health and reduce inflammation in MPN. The Mediterranean diet, characterized by increased consumption of extra virgin olive oil (EVOO), nuts, legumes, vegetables, fruits, fish, and whole grain products, has proven beneficial in modifying subclinical inflammation in diseases where chronic subclinical inflammation plays a key role (88). Specifically, the randomized interventional PREDIMED (Prevención con Dieta Mediterránea) study demonstrated that a Mediterranean diet supplemented with EVOO reduced the incidence of major cardiovascular events (89). Numerous longitudinal cohort studies show that a Mediterranean style eating pattern was associated with lower risk for cardiovascular disease (CVD), explained in part by reduction in CVD risk factors, most notably inflammation (90). We performed two pilot interventional studies to establish the feasibility of a Mediterranean diet in MPN (Mendez Luque et al, manuscript in preparation). We found that MPN patients can alter their diet toward a Mediterranean diet eating pattern (91). We did not observe significant changes in plasma inflammatory cytokines or gut microbiome over the 10-week intervention (92), although analysis was limited due to the small sample size. Upcoming studies with a larger cohort of MPN patients are required to rigorously test the impact of a Mediterranean diet on inflammatory biomarkers and symptom burden.

Approaching MPN as a disease that lies at the intersection of a neoplasm and chronic inflammatory disorder may better serve patients and the physicians who treat them. Addressing inflammation in MPN will likely reduce symptom burden, ameliorate some of the inflammation-driven morbidity associated with the disease, and potentially blunt disease progression. It is important, however, to note that other treatment modalities beyond reduction of inflammation are necessary to eradicate the neoplastic clone. Investigating MPN through the scientific lens of an inflammatory disease in addition to a cancer may reveal important aspects of MPN pathogenesis that may be missed by viewing MPN through cancer blinders.

ES and AF together wrote the article and edited it. ES created figures. All authors contributed to the article and approved the submitted version.