scholarly journals Significantly Upregulated Thrombo-Inflammatory Genes Are Normoregulated or Significantly Downregulated during Treatment with Interferon-Alpha2 in Patients with Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2978-2978 ◽  
Author(s):  
Vibe Skov ◽  
Caroline Riley ◽  
Mads Thomassen ◽  
Lasse Kjær ◽  
Thomas Stauffer Larsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Myeloproliferative Neoplasms ◽  
Inflammatory Genes ◽  
Chronic Myeloproliferative Neoplasms ◽  
Cell Counts ◽  
Increased Risk ◽  
Long Term Treatment ◽  
The Impact ◽  
First Time

Introduction: The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are associated with a high risk of arterial and venous thrombosis, which are attributed to several mechanisms, including elevated blood cell counts per se, in vivo leukocyte and platelet activation with increased adhesion of granulocytes, monocytes and platelets to each other and to a dysfunctional endothelium. In recent years, evidence has accumulated that chronic inflammation is an important pathogenetic mechanism for MPN-disease development and disease progression, inducing increasing genomic instability in hematopoietic cells and thereby emergence of additional mutations of significance for myelofibrotic and leukemic transformation. Recent studies have shown several thrombo-inflammatory genes to be upregulated in patients with MPNs, likely contributing to the increased risk of thrombosis. Several studies have documented that long term treatment with interferon-alpha2 (IFN) is able to normalize elevated cell counts in concert with induction of a remarkable decrease in the JAK2V617F allele burden and accordingly impacting important thrombosis promoting factors in MPNs. Herein, using whole blood gene expression profiling we for the first time report that treatment with IFN is able to normoregulate or significantly downregulate upregulated thrombo-inflammatory genes in patients with MPNs. Methods: Eight patients with ET, 21 patients with PV, and 4 patients with PMF participated in the study. All patients received treatment with IFN, in the large majority in a dosage ranging from 45-90 ug x 1 sc/week. Gene expression microarray analysis of whole blood was performed before and after 3 months of treatment. Total RNA was purified from whole blood, amplified to biotin-labeled RNA, and hybridized to Affymetrix HG-U133 2.0 Plus chips. Results: We identified 6261, 10,008, and 2828 probe sets to be significantly differentially expressed in ET, PV, and PMF, respectively, in response to treatment with IFN (pvalue < 0.05). Six thrombo-inflammatory genes were investigated: F3, PADI4, SELP, SERPINE1, SLC2A1, and THBS1. In all patients groups, the 6 genes were significantly upregulated at baseline and either normoregulated or significantly downregulated during treatment with IFN (Figure 1). Discussion and Conclusions: Thrombosis contributes significantly to morbidity and mortality in MPNs. Despite treatment with conventional drugs (hydroxyurea, anagrelide) - the most used cytoreductive therapies worldwide - patients with MPNs are still suffering potentially life-threatening or life-invalidating thrombotic complications in the brain, heart, lungs and elsewhere. Therefore, there is an urgent need for studies that explore the pathogenetic mechanisms eliciting the thrombotic state and the impact of novel therapies, such as IFN, upon the thrombogenic factors which might be operative. Herein, we have for the first time shown that IFN significantly downregulates several thrombo-inflammatory genes, known to be the upregulated in patients with concurrent or previous thrombosis. Highly intriguing, we found that IFN significantly downregulated the PADI4 gene, which is required for neutrophil extracellular trap (NET) formation and thrombosis development. A most recent study has shown neutrophils from patients with MPNs to be associated with an increase in NET formation, which was blunted by ruxolitinib. This study also showed that JAK2V617F-driven MPN mouse models have a NET-rich, prothrombotic phenotype, highlighting NETosis to be yet another important thrombosis mechanism in MPNs. In conclusion, we have for the first time shown 3 months IFN-treatment to be associated with a significant downregulation of upregulated thrombo-inflammatory genes, including significant downregulation of the NETosis associated gene - PADI4. In the context of a significantly increased risk of thrombosis after the MPN-diagnosis with a particular increased risk at 3 months, our results of significant downregulation of these thrombo-inflammatory genes during IFN-therapy are of paramount importance and may signal an advantage of IFN over conventional cytoreductive therapies. Further studies are required to decipher the impact of IFN upon upregulated thrombo-inflammatory genes and if combination therapy with ruxolitinib may be even more efficacious. Figure 1 Disclosures Hasselbalch: Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. OffLabel Disclosure: Interferon-alpha for treatment of myeloproliferative neoplasms

scholarly journals Highly Deregulated Fibulins in Patients with Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5396-5396
Author(s):  
Vibe Skov ◽  
Mads Thomassen ◽  
Lasse Kjær ◽  
Thomas Stauffer Larsen ◽  
Torben A Kruse ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Chronic Inflammation ◽  
Whole Blood ◽  
Myeloproliferative Neoplasms ◽  
Blood Gene Expression ◽  
Chronic Myeloproliferative Neoplasms ◽  
First Time

Introduction The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) develop in a biological continuum from the early cancer stages (ET/PV) to the advanced myelofibrosis stage characterized by huge splenomegaly, bone marrow failure and -fibrosis. Importantly, bone marrow fibrosis also increases from the early stages with reticulin fibrosis only and later deposition of mature collagen as well. Fibulins are glycoproteins that are important constituents of the extracellular matrix (ECM). Thus, fibulins have been shown to modulate cell morphology, growth, adhesion and motility. Dysregulation of fibulins has been reported in several cancers. In addition, upregulation of fibulins and elevated circulating fibulins have been reported in diseases - other than cancers -, in which chronic inflammation is an important pathogenetic factor, such as cardiovascular diseases. Thus, deregulated fibulins have been described in patients with type 2 diabetes mellitus. Herein, using whole blood gene expression profiling, we for the first time report deregulated fibulins in patients with MPNs. Aim To detect if genes associated with pre-atherosclerotic changes in type II diabetes are deregulated in patients with MPNs. Material and methods Gene expression microarrays were applied to generate gene expression profiles of whole blood from control subjects (n=21) and patients with ET (n=19), PV (n=41), and PMF (n=9). Total RNA was purified, amplified to biotin-labeled aRNA and hybridized to microarray chips. The statistical software R was applied to perform initial data processing and statistical analysis of gene expression changes between patients and control subjects. An FDR <0.05 was considered significant. Results We identified 23,657, 25,567, and 17,417 probe sets which were significantly differentially expressed between controls and patients with ET, PV, and PMF, respectively (FDR < 0.05). We focused upon the top 15 upregulated genes from a previous gene expression microarray study performed on arterial tissue from patients with type 2 diabetes compared to non-diabetic patients undergoing artery bypass graft surgery. Several of these genes were significantly deregulated in patients with MPNs (Table 1). In patients with ET, FBLN1, FBLN2,FAM107A, IGF2, MEG3, and ELN were significantly upregulated and ZFP36L2 were significantly downregulated. In patients with PV, FBLN1, FBLN2, ELN, LEPR, FAM107A, IGF2, CRISPLD2, and MEG3 were significantly upregulated and ZFP36L2 and SERPINF1 were significantly downregulated. In patients with PMF, MEG3, LEPR, FBLN1, FAM107A, ELN, IGF2, and VWF were significantly upregulated and ZFP36L2 and SERPINF1 were significantly downregulated. Discussion and conclusions Fibulins regulate several cellular functions including tissue homeostasis and remodeling after injury, angiogenesis, and tumorigenesis. Thus, fibulins have been reported to be upregulated in several cancer types, in which deregulated fibulins have been associated with cancer invasiveness and disease progression. We have for the first time shown that fibulins are also highly deregulated in patients with MPNs. The significance of our findings is presently unknown but since interactions between fibulins and transforming growth factor (TGFbeta) have been demonstrated, upregulated fibulins may enhance the capacities of TGFbeta, which shares several of the regulatory functions excerted by fibulins. In the context of chronic inflammation being a driving force for MPN development during the biological continuum from early cancer stages to the advanced myelofibrosis stage and chronic inflammation likely also accelerates the development of atherosclerosis in MPNs, it is highly intriguing to note that fibulins are also elevated in arteries from patients with type 2 diabetes mellitus. Thus, upregulated fibulins in blood cells may actually indirectly reflect ongoing matrix modelling during atherosclerosis development, including remodeling and turnover of basement membranes in the inflamed endothelium. In conclusion, highly deregulated fibulins have been demonstrated in circulating blood cells by whole blood gene expression profiling. Further studies are needed to assess the significance of our findings in terms of potential associations to modelling of ECM in the bone marrow and during development of atherosclerosis in MPNs. Disclosures Hasselbalch: Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board.

scholarly journals Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chen Yao ◽  
Roby Joehanes ◽  
Rory Wilson ◽  
Toshiko Tanaka ◽  
Luigi Ferrucci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Dna Methylation ◽  
Cigarette Smoking ◽  
Association Study ◽  
Whole Blood ◽  
Lung Diseases ◽  
Epigenetic Modification ◽  
Blood Gene Expression ◽  
Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

Tet2 Loss Accelerates The Myeloproliferative Neoplasm (MPN) Phenotype Of Jak2V617F Knockin Mice But Is Insufficient To Cause Leukemic Transformation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4095-4095
Author(s):  
Edwin Chen ◽  
Lawrence J Breyfogle ◽  
Rebekka K. Schneider ◽  
Luke Poveromo ◽  
Ross L. Levine ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Conditional Knockout ◽  
The Other ◽  
Myelogenous Leukemia ◽  
Leukemic Transformation ◽  
The Impact

Abstract TET2 mutations are early somatic events in the pathogenesis of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN) and are one of the most common genetic lesions found in these diseases. In MPN, TET2 mutations are enriched within more advanced disease phenotypes such as myelofibrosis and leukemic transformation and often co-occur with the JAK2V617F mutation, which is present in the majority of MPN patients. We have developed and characterized a Jak2V617F conditional knockin mouse (Jak2VF/+), the phenotype of which closely recapitulates the features of human MPN. To determine the impact of Tet2 loss on Jak2V617F-mediated MPN, we crossed Tet2 conditional knockout mice with Jak2VF/+ knockin and Vav-Cre transgenic mice and backcrossed the compound mutant animals. We then characterized the effects of heterozygous and homozygous loss of Tet2 on the phenotype of Jak2VF/+ mice. We assessed peripheral blood counts, histopathology, hematopoietic differentiation using flow cytometry, colony formation and re-plating capacity. We also evaluated the effects of Tet2 loss on the transcriptome of the HSC compartment using gene expression microarrays and on HSC function using competitive bone marrow transplantation assays. Similar to Jak2VF/+/VavCre+ mice, Tet2+/-/Jak2VF/+/VavCre+ and Tet2-/-/Jak2VF/+/VavCre+ mice develop leukocytosis, elevated hematocrits (HCT) and thrombocytosis. Tet2-/-/Jak2VF/+/VavCre+ mice demonstrate enhanced leukocytosis and splenomegaly compared to the other groups. All groups demonstrate myeloid expansion, erythroid hyperplasia and megakaryocytic abnormalities consistent with MPN in the bone marrow and spleen, while more prominent myeloid expansion and megakaryocytic morphological abnormalities are observed in Tet2-/-/Jak2VF/+/VavCre+ mice as compared to the other groups. Notably, we do not see the development of acute myelogenous leukemia (AML) in Tet2-/-/Jak2VF/+/VavCre+ mice at 6 months. We see enhanced expansion of lineagelowSca1+cKithigh (LSK) cells (enriched for HSC) most prominently in the spleens of Tet2+/-/Jak2VF/+/VavCre+ and Tet2-/-/Jak2VF/+/VavCre+ mice as compared to Jak2VF/+/VavCre+ mice. In colony forming assays, we find that Tet2-/-/Jak2VF/+/VavCre+ LSK cells have enhanced re-plating activity compared to Jak2VF/+/VavCre+ LSK cells and that Tet2-/-/Jak2VF/+/VavCre+ LSK cells form more colonies that Tet2-/-/Jak2+/+/VavCre+ cells. Gene expression analysis demonstrates enrichment of a HSC self-renewal signature inTet2-/-/Jak2VF/+/VavCre+ LSK cells. Concordant with this, we find that Tet2-/-/Jak2VF/+/VavCre+ LSK cells have enhanced competitive repopulation at 16 weeks as compared to Jak2VF/+/VavCre+ and Tet2+/-/Jak2VF/+/VavCre+ LSK cells. In aggregate these findings demonstrate that Tet2 loss promotes disease progression in MPN but is insufficient to drive full leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

Medical Consequences of Long-term Treatment of Acromegaly

2010 ◽  
Vol 06 ◽  
pp. 68
Author(s):  
Rosario Pivonello ◽  
Renata S Auriemma ◽  
Mariano Galdiero ◽  
Ludovica FS Grasso ◽  
Annamaria Colao ◽  
...  
Keyword(s):  
Signs And Symptoms ◽  
Premature Death ◽  
Term Treatment ◽  
Tumour Mass ◽  
Risk Of Death ◽  
Increased Risk ◽  
Long Term Treatment ◽  
A Minor ◽  
The Impact

This article discusses the impact of long-term treatment of acromegaly on cardiovascular, metabolic, respiratory and articular complications as well as on malignancies. The main goals of treatment of acromegaly include normalisation of biochemical markers of disease activity, improvement in signs and symptoms of the disease, removal or reduction of tumour mass and preservation of pituitary function, together with prevention of complications. Cardiovascular and respiratory complications are the main causes of morbidity and mortality, whereas neoplasms are a minor cause of increased risk of death. Other associated diseases are arthropathy, carpal tunnel syndrome and reproductive disorders. The prolonged elevation of growth hormone (GH) and insulin-like growth factor (IGF)-I levels results in premature death, whereas strong biochemical control improves wellbeing and restores life expectancy to normal.

scholarly journals Philadelphia-Negative Chronic Myeloproliferative Neoplasms during the COVID-19 Pandemic: Challenges and Future Scenarios

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4750
Author(s):  
Francesca Palandri ◽  
Massimo Breccia ◽  
Valerio De Stefano ◽  
Francesco Passamonti
Keyword(s):  
Hematological Malignancies ◽  
Myeloproliferative Neoplasms ◽  
Published Data ◽  
Future Scenarios ◽  
Risk Of Infection ◽  
Immunosuppressive Activity ◽  
Chronic Myeloproliferative Neoplasms ◽  
Increased Risk ◽  
Abrupt Discontinuation ◽  
Case Basis

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) started in December 2019 in China and then become pandemic in February 2020. Several publications investigated the possible increased rate of COVID-19 infection in hematological malignancies. Based on the published data, strategies for the management of chronic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are provided. The risk of severe COVID-19 seems high in MPN, particularly in patients with essential thrombocythemia, but not negligible in myelofibrosis. MPN patients are at high risk of both thrombotic and hemorrhagic complications and this must be accounted in the case of COVID-19 deciding on a case-by-case basis. There are currently no data to suggest that hydroxyurea or interferon may influence the risk or severity of COVID-19 infection. Conversely, while the immunosuppressive activity of ruxolitinib might pose increased risk of infection, its abrupt discontinuation during COVID-19 syndrome is associated with worse outcome. All MPN patients should receive vaccine against COVID-19; reassuring data are available on efficacy of mRNA vaccines in MPNs.

scholarly journals Reasons for immunologic inefficiency of antiretroviral therapy in patients with HIV

2014 ◽  
Vol 95 (4) ◽  
pp. 581-588 ◽  
Author(s):  
A F Oleynik ◽  
V Kh Fazylov
Keyword(s):  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Highly Active Antiretroviral Therapy ◽  
Immunological Response ◽  
Response To Treatment ◽  
Highly Active ◽  
Cell Counts ◽  
Increased Risk ◽  
Long Term Treatment ◽  
Cd4 Lymphocytes

The main component of the treatment of patients with HIV infection is highly active antiretroviral therapy (HAART), which can help to control the disease. The main goal of HAART is to increase the life duration and to maintain the quality of patients’ life. Improved survival among HIV-infected patients receiving highly active antiretroviral therapy is achieved mainly by a decrease of HIV RNA viral load, which increases CD4 lymphocytes count. However, some patients may present with discordant response to treatment, when there is no CD4 lymphocyte count elevation associated with the virus disappearing from the blood. Such patients retain immunodeficiency, despite long-term treatment. The risk of opportunistic infections on the background of insufficient immunological response, despite viral replication suppression, is higher than in patients with good immunological response to treatment. Consistently low CD4 cell counts are associated with an increased risk of AIDS diagnosis. Furthermore, this group of patients shows a slight increase in mortality not associated with AIDS-defining illnesses. The reasons for the low CD4 lymphocytes count increase in some patients achieving virologic response to HAART remain unclear. The immunological efficacy of treatment depends on many factors: baseline CD4 count, duration of HIV infection prior to HAART initiation, age, co-infection with HCV, presence of secondary diseases and comorbidities, HAART regimens, IL-2 use and others. Literature review covers the phenomenon of immunological «non-response» to HAART, factors leading to its development, and possible methods of correction. Currently, there are more questions than answers in the area of immunological non-effectiveness of HAART in HIV-infected patients.

scholarly journals Changes in gene expression induced by Micro-Immunotherapy

2021 ◽  
Vol 11 (40) ◽  
pp. 154-155
Author(s):  
Capieaux Etienne ◽  
Donat De Groote ◽  
Pierre Dorfman ◽  
Maurice Jeaner
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Dna Microarray ◽  
Interleukin 1 ◽  
Interleukin 2 ◽  
Diabetic Patients ◽  
Mrna Levels ◽  
Microarray Technology ◽  
Increased Risk ◽  
The Impact

Background: Metabolic syndrome (MS) is a metabolic disorder associated with obesity, type-II diabetes, and “low grade inflammation”, with the concomitant increased risk of cardiovascular events. As a chronic inflammatory process, MS results in a dysregulation of the cytokine profile. 2L®INFLAM, a Micro-immunotherapy (MI) medication formulated with highly diluted cytokines, is currently prescribed in Belgium for inflammatory diseases and potentially may be helpful for MS patients. Aims: To investigate the impact of 2L®INFLAM on selected gene expression markers (mRNA) in patients suffering from MS, in addition to biological and clinical parameters. Methodology: Four well characterized MS adult patients with stabilized body-weight were advised to take one capsule of 2L®INFLAM per day (by sublingual-oral route) for 6 months (composition in table 1). Concomitantly to biological and clinical examination, genes expression status was assessed by a DNA microarray technology (Oxygen™) comprising 200 genes involved mainly in oxidative stress and inflammation. Whole blood collection was performed before and after treatment (3-6 months) and mRNA levels measured. Gene expression was classified in 3 series (normally expressed, up or down-regulated) and genes related to diabetes predisposition were scored by using a proprietary Diascore (Probiox). Results: Before MI medication, a significant percentage of dysregulated genes (median: 16.3%) as well as a positive Diascore (median: 1.6) were noticed. Impressive correction of dysregulated genes (reaching 90% for one patient) was observed after 3 months of treatment (median: 2.3%) in addition to an improvement of Diascore in 3 MS patients out of 4 (median: 0.5). During the same period, both clinical and biological parameters remained unchanged. Conclusions: MS patients showing a high level of gene dysregulation efficiently normalized after 3 months of 2L®INFLAM (64%-90%), suggesting a biological regulatory effect of MI and a potential benefit of this medication for diabetic patients. Up and down-deregulated gene profiles were specific for each patient and not related to cytokine components of the formula. These preliminary data support the “domino effect” of MI sequential formula to restore in depth the immune homeostasis. DNA microarray technology may represent a promising tool for new provings as well as for biochemical comprehension of the “in vivo” effectiveness of highly diluted immune messengers. Table 1: 2L®INFLAM composition Compounds Dilutions Interleukin-1 (IL-1): 17 CH* Interleukin-1 Ra (IL-1 Ra): 3 CH Interleukin-2 (IL-2): 9 CH Interleukin-4 (IL-4): 7 CH Interleukin-6 (IL-6): 9 CH Interleukin-8 (IL-8): 9 CH Interleukin-10 (IL-10): 4 CH Interleukin-13 (IL-13): 9 CH Ciliary Neuro Trophic Factor (CNTF): 17 CH Leukemia Inhibitory Factor (LIF): 17 CH Oncostatine M (OSM): 9 CH Platelet Derived Growth Factor (PDGF): 5 CH Prostaglandine E2 (PgE2): 200 K** Rantes (Rantes): 17 CH Transforming Growth Factor beta(TGFβ): 5 CH Tumor Necrosis Factor α (TNFα): 17 CH SNA INFLAMa-01 18 C SNA INFLAMb-01 18 CH * CH: Centesimal Hahnemannian (1/100) ** K: Centesimal Korsakovian (1/100)

scholarly journals Risks of Solid and Lymphoid Malignancies in Patients with Myeloproliferative Neoplasms: Clinical Implications

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3061
Author(s):  
Mette Brabrand ◽  
Henrik Frederiksen
Keyword(s):  
General Population ◽  
Myeloproliferative Neoplasms ◽  
Cancer Prognosis ◽  
Control Group ◽  
Solid Cancer ◽  
Cancer Risks ◽  
Hematological Cancer ◽  
Chronic Myeloproliferative Neoplasms ◽  
Lymphoid Malignancies ◽  
Increased Risk

In the past decade, several studies have reported that patients with chronic myeloproliferative neoplasms (MPNs) have an increased risk of second solid cancer or lymphoid hematological cancer. In this qualitative review study, we present results from studies that report on these cancer risks in comparison to cancer incidences in the general population or a control group. Our literature search identified 12 such studies published in the period 2009–2018 including analysis of more than 65,000 patients. The results showed that risk of solid cancer is 1.5- to 3.0-fold elevated and the risk of lymphoid hematological cancer is 2.5- to 3.5-fold elevated in patients with MPNs compared to the general population. These elevated risks apply to all MPN subtypes. For solid cancers, particularly risks of skin cancer, lung cancer, thyroid cancer, and kidney cancer are elevated. The largest difference in cancer risk between patients with MPN and the general population is seen in patients below 80 years. Cancer prognosis is negatively affected due to cardiovascular events, thrombosis, and infections by a concurrent MPN diagnosis mainly among patients with localized cancer. Our review emphasizes that clinicians caring for patients with MPNs should be aware of the very well-documented increased risk of second non-myeloid cancers.

Increase in circulating CD4+CD25+Foxp3+ T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2170-2173 ◽  
Author(s):  
Caroline Hasselbalch Riley ◽  
Morten Krogh Jensen ◽  
Marie Klinge Brimnes ◽  
Hans Carl Hasselbalch ◽  
Ole Weis Bjerrum ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Myeloproliferative Neoplasms ◽  
Term Treatment ◽  
Immune Reactivity ◽  
Chronic Myeloproliferative Neoplasms ◽  
Healthy Donors ◽  
Long Term Treatment ◽  
And Function

Abstract Recent reports have described complete or major molecular remission in patients with polycythemia vera after long-term treatment with the immunomodulatory agent IFN-α2. Accordingly, there are reasons to believe that the immune system is a key player in eradicating the JAK2 mutated clone in these patients. Foxp3+ regulatory T cells play a pivotal role in maintaining immune homeostasis and, importantly, preventing immune reactivity to self-antigens; however, their suppressive activity can compromise an effective antitumor immune response, and high frequencies of regulatory T cells in peripheral blood have been reported in both hematologic and solid cancers. We have analyzed the number, phenotype, and function of circulating CD4+CD25+Foxp3+ T cells in patients with chronic myeloproliferative neoplasms. Surprisingly, we found a marked expansion of this subset of lymphocytes in patients treated with IFN-α2 (13.0%; 95% confidence interval [CI] 10.8% to 15.2%) compared with healthy donors (6.1%; 95% CI 4.9% to 7.2%), patients with untreated chronic myeloproliferative neoplasms (6.9%; 95% CI 5.8% to 7.4%), or patients treated with hydroxyurea (5.8%; 95% CI 4.3% to 7.4%; P < .0001).

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