Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.

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Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR–ABL-Negative Myeloproliferative Neoplasm

Antioxidants ◽

10.3390/antiox9111037 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1037

Author(s):

Alessandro Allegra ◽

Giovanni Pioggia ◽

Alessandro Tonacci ◽

Marco Casciaro ◽

Caterina Musolino ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cell ◽

Chronic Inflammation ◽

Myeloproliferative Neoplasms ◽

Myeloproliferative Neoplasm ◽

Tumor Stage ◽

Driver Mutations ◽

Hematopoietic Stem ◽

Chronic Myeloproliferative Neoplasms ◽

Inflammatory State

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have recently been revealed to be related to chronic inflammation, oxidative stress, and the accumulation of reactive oxygen species. It has been proposed that MPNs represent a human inflammation model for tumor advancement, in which long-lasting inflammation serves as the driving element from early tumor stage (over polycythemia vera) to the later myelofibrotic cancer stage. It has been theorized that the starting event for acquired stem cell alteration may occur after a chronic inflammation stimulus with consequent myelopoietic drive, producing a genetic stem cell insult. When this occurs, the clone itself constantly produces inflammatory components in the bone marrow; these elements further cause clonal expansion. In BCR–ABL1-negative MPNs, the driver mutations include JAK 2, MPL, and CALR. Transcriptomic studies of hematopoietic stem cells from subjects with driver mutations have demonstrated the upregulation of inflammation-related genes capable of provoking the development of an inflammatory state. The possibility of acting on the inflammatory state as a therapeutic approach in MPNs appears promising, in which an intervention operating on the pathways that control the synthesis of cytokines and oxidative stress could be effective in reducing the possibility of leukemic progression and onset of complications.

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Expression of CD markers in JAK2V617F positive myeloproliferative neoplasms: Prognostic significance

Oncology Reviews ◽

10.4081/oncol.2018.373 ◽

2018 ◽

Author(s):

Saeid Shahrabi ◽

Ali Ehsanpour ◽

Somayyeh Heidary ◽

Mohammad Shahjahani ◽

Masumeh Maleki Behzad

Keyword(s):

Clinical Outcomes ◽

Prognostic Biomarker ◽

Myeloproliferative Neoplasms ◽

Expression Patterns ◽

Prognostic Significance ◽

Leukemic Transformation ◽

And Function ◽

The Relationship ◽

Cd Markers

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by the presence of JAK2V617F mutation. Thrombohemorrhagic as well as autoimmune or inflammatory phenomena are common clinical outcomes of these disorders. Recent studies have shown that abnormality in frequency and function of blood cells manifested by an alteration in CD markers’ expression patterns play a key role in these complications. So, there may be a relationship between CD markers’ expressions and prognosis of JAK2V617F positive MPNs. Therefore, in this review, we have focused on these abnormalities from the perspective of changing expressions of CD markers and assessment of the relationship between these changes with prognosis of JAK2V617F positive MPNs. It can be stated that the abnormal expression of a large number of CD markers can be used as a prognostic biomarker for clinical outcomes including thrombohememorrhagic events, as well as autoimmune and leukemic transformation in JAK2V617F positive MPNs. Considering the possible role of CD markers’ expressions in JAK2V617F MPNs prognosis, further studies are needed to confirm the relationship between the expression of CD markers with prognosis to be able to find an appropriate therapeutic approach via targeting CD markers.

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What are the current treatment approaches for patients with polycythemia vera and essential thrombocythemia?

Hematology ◽

10.1182/asheducation-2017.1.480 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 480-488 ◽

Cited By ~ 6

Author(s):

Alessandro M. Vannucchi ◽

Paola Guglielmelli

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

State Of The Art ◽

Myeloproliferative Neoplasms ◽

Symptom Burden ◽

Current Treatment ◽

Interferon Α ◽

Jak2 Inhibitor ◽

Chronic Myeloproliferative Neoplasms

Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom burden, and impaired survival mainly due to thrombosis, progression to myelofibrosis, and transformation to acute leukemia. In this manuscript, we will review the most recent changes in diagnostic criteria, the improvements in risk stratification, and the “state of the art” in the daily management of these disorders. The role of conventional therapies and novel agents, interferon α and the JAK2 inhibitor ruxolitinib, is critically discussed based on the results of a few basic randomized clinical studies. Several unmet needs remain, above all, the lack of a curative approach that might overcome the still burdensome morbidity and mortality of these hematologic neoplasms, as well as the toxicities associated with therapeutic agents.

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Molecular insights into regulation of JAK2 in myeloproliferative neoplasms

Blood ◽

10.1182/blood-2015-01-621110 ◽

2015 ◽

Vol 125 (22) ◽

pp. 3388-3392 ◽

Cited By ~ 39

Author(s):

Olli Silvennoinen ◽

Stevan R. Hubbard

Keyword(s):

Molecular Characterization ◽

Human Disease ◽

Molecular Mechanisms ◽

Myeloproliferative Neoplasms ◽

Critical Role ◽

Hematologic Malignancies ◽

Janus Kinase ◽

Constitutive Activation

Abstract The critical role of Janus kinase-2 (JAK2) in regulation of myelopoiesis was established 2 decades ago, but identification of mutations in the pseudokinase domain of JAK2 in myeloproliferative neoplasms (MPNs) and in other hematologic malignancies highlighted the role of JAK2 in human disease. These findings have revolutionized the diagnostics of MPNs and led to development of novel JAK2 therapeutics. However, the molecular mechanisms by which mutations in the pseudokinase domain lead to hyperactivation of JAK2 and clinical disease have been unclear. Here, we describe recent advances in the molecular characterization of the JAK2 pseudokinase domain and how pathogenic mutations lead to constitutive activation of JAK2.

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The possible role of mutated endothelial cells in myeloproliferative neoplasms

Haematologica ◽

10.3324/haematol.2021.278499 ◽

2021 ◽

Author(s):

Mirko Farina ◽

Domenico Russo ◽

Ronald Hoffman

Keyword(s):

Myeloproliferative Neoplasms ◽

Hematopoietic Cells ◽

Clinical Manifestations ◽

Vascular Complications ◽

Hematologic Malignancies ◽

Driver Mutations ◽

Vascular Events ◽

Hematopoietic Stem ◽

High Incidence

Myeloproliferative neoplasms (MPN) are chronic, clonal hematologic malignancies characterized by myeloproliferation and a high incidence of vascular complications (thrombotic and bleeding). Although MPN-specific driver mutations have been identified, the underlying events that culminate in these clinical manifestations require further clarification. We reviewed the numerous studies performed during the last decade identifying endothelial cell (EC) dysregulation as a factor contributing to MPN disease development. The JAK2V617F MPN mutation and other myeloid-associated mutations have been detected not only in hematopoietic cells but also in EC and their precursors in MPN patients, suggesting a link between mutated EC and the high incidence of vascular events. To date, however, the role of EC in MPN continues to be questioned by some investigators. In order to further clarify the role of EC in MPN, we first describe the experimental strategies used to study EC biology and then analyze the available evidence generated using these assays which implicate mutated EC in MPN-associated abnormalities. Mutated EC have been reported to possess a pro-adhesive phenotype as a result of increased endothelial Pselectin exposure, secondary to degranulation of Weibel-Palade bodies, which is further accentuated by exposure to pro-inflammatory cytokines. Additional evidence indicates that MPN myeloproliferation requires JAK2V617F expression by both hematopoietic stem cells and EC. Furthermore, the reports of JAK2V617F and other myeloid malignancy- associated mutations in both hematopoietic cells and EC in MPN patients support the hypothesis that MPN driver mutations may first appear in a common precursor cell for both EC and hematopoietic cells.

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The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome

Cells ◽

10.3390/cells10102597 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2597

Author(s):

Elena Masselli ◽

Giulia Pozzi ◽

Cecilia Carubbi ◽

Marco Vitale

Keyword(s):

Disease Risk ◽

Phenotypic Diversity ◽

Myeloproliferative Neoplasms ◽

Hematologic Malignancies ◽

Response To Therapy ◽

Germline Variants ◽

Functional Perspective ◽

Large Patient ◽

Malignant State ◽

Host Genetic

Myeloproliferative neoplasms are hematologic malignancies typified by a substantial heritable component. Germline variants may affect the risk of developing a MPN, as documented by GWAS studies on large patient cohorts. In addition, once the MPN occurred, inherited host genetic factors can be responsible for tuning the disease phenotypic presentation, outcome, and response to therapy. This review covered the polymorphisms that have been variably associated to MPNs, discussing them in the functional perspective of the biological pathways involved. Finally, we reviewed host genetic determinants of clonal hematopoiesis, a pre-malignant state that may anticipate overt hematologic neoplasms including MPNs.

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Organ Stiffness in the Work-Up of Myelofibrosis and Philadelphia-Negative Chronic Myeloproliferative Neoplasms

Journal of Clinical Medicine ◽

10.3390/jcm9072149 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2149

Author(s):

Edoardo Benedetti ◽

Rita Tavarozzi ◽

Riccardo Morganti ◽

Benedetto Bruno ◽

Emilia Bramanti ◽

...

Keyword(s):

Myeloproliferative Neoplasms ◽

Liver Stiffness ◽

Progression Free Survival ◽

Clinical Work ◽

Healthy Controls ◽

Chronic Myeloproliferative Neoplasms ◽

Risk Of Progression ◽

Spleen Stiffness ◽

Work Up

To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV (p = 0.9); however, both MF and PV groups had significantly higher SS than the ET group (p = 0.011 and p = 0.035, respectively) and healthy controls (p < 0.0001 and p = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) (p = 0.012; HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) (p < 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) (p < 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively (p = 0.038; HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls (p = 0.001), but not between the patient cohorts with ET and PV and healthy controls (p = 0.999 and p = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression.

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Emerging Role of Neutrophils in the Thrombosis of Chronic Myeloproliferative Neoplasms

International Journal of Molecular Sciences ◽

10.3390/ijms22031143 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1143

Author(s):

Francisca Ferrer-Marín ◽

Ernesto José Cuenca-Zamora ◽

Pedro Jesús Guijarro-Carrillo ◽

Raúl Teruel-Montoya

Keyword(s):

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

The Novel ◽

Jak Inhibitors ◽

Chronic Myeloproliferative Neoplasms ◽

Activated Neutrophils ◽

Thrombotic Complications ◽

Novel Therapeutic Strategies ◽

Ideal Matrix

Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.

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Immune Phenomena in Myeloid Neoplasms: An “Egg or Chicken” Question

Frontiers in Immunology ◽

10.3389/fimmu.2021.751630 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wilma Barcellini ◽

Bruno Fattizzo

Keyword(s):

Myeloid Leukemia ◽

Myeloproliferative Neoplasms ◽

Bone Marrow Failure ◽

Chronic Myeloproliferative Neoplasms ◽

Myeloid Neoplasms ◽

Autoimmune Cytopenias ◽

Immune Phenomena ◽

Autoimmune Phenomena ◽

Epidemiological Association

Immune phenomena are increasingly reported in myeloid neoplasms, and include autoimmune cytopenias/diseases and immunodeficiency, either preceding or complicating acute myeloid leukemia, myelodysplastic syndromes (MDS), chronic myeloproliferative neoplasms, and bone marrow failure (BMF) syndromes. Autoimmunity and immunodeficiency are the two faces of a dysregulated immune tolerance and surveillance and may result, along with contributing environmental and genetic factors, in an increased incidence of both tumors and infections. The latter may fuel both autoimmunity and immune activation, triggering a vicious circle among infections, tumors and autoimmune phenomena. Additionally, alterations of the microbiota and of mesenchymal stem cells (MSCs) pinpoint to the importance of a permissive or hostile microenvironment for tumor growth. Finally, several therapies of myeloid neoplasms are aimed at increasing host immunity against the tumor, but at the price of increased autoimmune phenomena. In this review we will examine the epidemiological association of myeloid neoplasms with autoimmune diseases and immunodeficiencies, and the pivotal role of autoimmunity in the pathogenesis of MDS and BMF syndromes, including the paroxysmal nocturnal hemoglobinuria conundrum. Furthermore, we will briefly examine autoimmune complications following therapy of myeloid neoplasms, as well as the role of MSCs and microbiota in these settings.

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MicroRNA-146a Deficiency Leads to Increased Myeloid Cell Proliferation and Activation

Blood ◽

10.1182/blood.v118.21.2815.2815 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2815-2815

Author(s):

Jimmy L. Zhao ◽

Dinesh S. Rao ◽

Mark Boldin ◽

Konstantin Taganov ◽

David Baltimore

Keyword(s):

Bone Marrow ◽

Bone Marrow Cells ◽

Myeloid Cell ◽

Hematologic Malignancies ◽

Negative Regulator ◽

Myeloproliferative Disease ◽

Hematopoietic System ◽

Inflammatory State ◽

Important Negative Regulator

Abstract Abstract 2815 NF-κB is a key regulator of inflammation and the immune activation against pathogens. On the other hand, constitutive and dysregulated NF-κB activation has been shown to lead to hematologic malignancies. Thus, NF-κB activity has to be properly regulated to achieve this delicate balance. Recent studies on microRNA-146a (miR-146a) suggest it to be an important negative regulator of NF-κB activation by targeting TRAF6 and IRAK1. To characterize the function of miR-146a in the context of NF-κB activation in the hematopoietic system, we have created a knockout (KO) mouse with germline deletion of miR-146a gene. We have shown that over time miR-146a KO mice develop a myeloproliferative condition in spleen and bone marrow that progresses to splenic myeloid sarcoma and bone marrow fibrosis. The myeloproliferative disease is driven by dysregulated NF-κB activation as the KO spleen and bone marrow cells show increased NF-κB activity and reduction in NF-κB level effectively rescues the myeloproliferative disease. In addition, the KO mice exhibit a chronic inflammatory state with increased cytokine production and macrophages from the KO are hyper-activated upon primary LPS stimulation and secondary re-stimulation. In this study, we have provided genetic evidence that miR-146a functions as a tumor suppressor in the hematopoietic system and highlighted the important role of miR-146a as a negative regulator of NF-κB activation and inflammation. Disclosures: Taganov: Regulus Therapeutics Inc: Employment.

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