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?

Abstract

The morbidity and mortality of patients with the chronic Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis are mainly caused by cardiovascular diseases, thrombohemorrhagic complications, and bone marrow failure because of myelofibrosis and leukemic transformation. In the general population, chronic inflammation is considered of major importance for the development of atherosclerosis and cancer. MPNs are characterized by a state of chronic inflammation, which is proposed to be the common denominator for the development of "premature atherosclerosis," clonal evolution, and second cancer in patients with MPNs. Chronic inflammation may both initiate clonal evolution and catalyze its expansion from early disease stage to the myelofibrotic burnt-out phase. Furthermore, chronic inflammation may also add to the severity of cardiovascular disease burden by accelerating the development of atherosclerosis, which is well described and recognized in other chronic inflammatory diseases. A link between chronic inflammation, atherosclerosis, and second cancer in MPNs favors early intervention at the time of diagnosis (statins and interferon-␣2), the aims being to dampen chronic inflammation and clonal evolution and thereby also diminish concurrent diseasemediated chronic inflammation and its consequences (accelerated atherosclerosis and second cancer).

Aberrant DNA methylation profile of chronic and transformed classic Philadelphia-negative myeloproliferative neoplasms

“…This observation is in accordance with the fact that MPNs are characterized by a state of chronic inflammation, proposed as the common denominator for the clinical evolution and secondary cancer in patients with MPNs. 48 Transcription factors such as LMO2 were also identified as aberrantly methylated in transformed samples. 49 In conclusion, our results indicate that: 1) the three types of MPNs analyzed in our study show a distinct DNA methylation signature from healthy donors, but the same pattern of aberrant DNA methylation among pathologies, and, therefore, changes in DNA methylation, can not explain the differences in phenotype of these three entities; 2) genes differentially methylated in MPNs could be involved in the pathogenesis of these diseases, for example, by deregulating the NF-κB pathway; 3) MPNs transformed to acute leukemia have an increased number of differentially methylated genes compared to MPNs in chronic phase, and these genes overlap with those seen in primary AML; and 4) differential DNA methylation of IFN pathway genes may play a role in disease progression.…”

CMML: Clinical and molecular aspects

“…A history of infection or inflammatory condition is associated with an increased risk of CMML [33], raising intriguing questions as to the connection between inflammation in the bone marrow milieu and clonal emergence or selection amongst HSCs [34]. Conversely, abnormal immune populations may be present in MDS and CMML.…”

Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

“…Furthermore, ruxolitinib has no or minor impact on the malignant clone but primarily on the inflammatory process associated with MPNs. Thus, we suggest that CT targeting both the malignant clone (IFNα2) and the inflammatory state (ruxolitinib) may be superior to monotherapy with ruxolitinib as described in most recent reviews 2, 21, 23…”

“…The hypothesized role of chronic inflammation in the progression of MPN and in attenuating the efficacy of IFNα2 implies that combination therapy (CT) with IFNα2 and ruxolitinib may be a rational strategy in patients with MPN 2, 20, 21. This approach may also improve tolerability of IFNα2 by allowing a lower dosage and reducing the inflammation‐mediated adverse effects.…”