Malignant JAK-signaling: at the interface of inflammation and malignant transformation

Posted on March 31, 2025March 31, 2025 by mpn_admin

March 26, 2025

Florian Perner, Heike L. Pahl, Robert Zeiser & Florian H. Heidel

Abstract

The JAK pathway is central to mammalian cell communication, characterized by rapid responses, receptor versatility, and fine-tuned regulation. It involves Janus kinases (JAK1, JAK2, JAK3, TYK2), which are activated when natural ligands bind to receptors, leading to autophosphorylation and activation of STAT transcription factors [1, 2]. JAK-dependent signaling plays a pivotal role in coordinating cell communication networks across a broad spectrum of biological systems including development, immune responses, cell growth, and differentiation. JAKs are frequently mutated in the aging hematopoietic system [3, 4] and in hematopoietic cancers [5]. Thus, dysregulation of the pathway results in various diseases, including cancers and immune disorders. The binding of extracellular ligands to class I and II cytokine receptors initiates a critical signaling cascade through the activation of Janus kinases (JAKs). Upon ligand engagement, JAKs become activated and phosphorylate specific tyrosine residues on the receptor, creating docking sites for signal transducer and activator of transcription (STAT) proteins. Subsequent JAK-mediated phosphorylation of STATs enables their dimerization and nuclear translocation, where they function as transcription factors to modulate gene expression. Under physiological conditions, JAK-signaling is a tightly regulated mechanism that governs cellular responses to external cues, such as cytokines and growth factors, ensuring homeostasis and maintaining the functional integrity of tissues and organs. Highly defined regulation of JAK-signaling is essential for balancing cellular responses to inflammatory stimuli and growth signals, thus safeguarding tissue health. In contrast, dysregulated JAK-signaling results in chronic inflammation and unrestrained cellular proliferation associated with various diseases. Understanding the qualitative and quantitative differences at the interface of physiologic JAK-signaling and its aberrant activation in disease is crucial for the development of targeted therapies that precisely tune this pathway to target pathologic activation patterns while leaving homeostatic processes largely unaffected. Consequently, pharmaceutical research has targeted this pathway for drug development leading to the approval of several substances with different selectivity profiles towards individual JAKs. Yet, the precise impact of inhibitor selectivity and the complex interplay of different functional modules within normal and malignant cells remains incompletely understood. In this review, we summarize the current knowledge on JAK-signaling in health and disease and highlight recent advances and future directions in the field.

Thrombosis and Inflammation Drive Mortality and Cancer Risk in Myeloproliferative Disorders

Posted on November 19, 2024November 19, 2024 by mpn_admin

November 15, 2024

Lisa Kuhns, PhD, MD

Despite the advancements in treatment, thrombosis remains a significant challenge for patients with myeloproliferative neoplasms (MPNs), contributing to increased mortality and the development of secondary cancers, according to an article published in Blood Cancer Journal.

“These risks arise from disease-related clonal hematopoiesis and subsequent chronic systemic inflammation, leading to thrombosis and genetic instability,” explained Tiziano Barbui, FROM, Fondazione per la Ricerca Ospedale di Bergamo ETS, Bergamo, Italy, and coauthors. “In our large databases of patients with MPN, we investigated the incidence and risk factors of thrombosis that may explain this association, culminating in an increased risk of mortality.”

Recent research has highlighted the persistent risk of thrombotic events in patients with classic MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These disorders are characterized by a high incidence of both arterial and venous thrombosis, which complicates patient management and contributes to disease progression. Notably, studies indicate that approximately 20% of MPN diagnoses are heralded by thrombotic events, with ongoing risks observed over time.

A large-scale study involving more than 9000 patients with MPN revealed significantly elevated hazard ratios for thrombotic events compared with matched controls. Specifically, arterial thrombosis hazard ratios were 3.0 at 3 months and 2.0 at 1 year postdiagnosis. Venous thrombosis rates were even more alarming, with hazard ratios of 9.7 at 3 months and 4.7 at 1 year. While conventional treatments such as hydroxyurea have demonstrated efficacy in reducing arterial thrombosis, their impact on venous events is less pronounced.

The implications of these findings extend beyond immediate health risks and suggest a potential link between thrombosis and progression to more severe forms of MPNs, such as myelofibrosis and acute leukemia. In particular, arterial thrombosis has been identified as an independent predictor of increased mortality in patients with ET and PV. For instance, a multistate model analysis indicated that patients experiencing arterial thrombosis had a 25% increase in mortality risk compared with those without such events.

Emerging evidence also suggests that thrombosis may be associated with an increased risk of developing secondary cancers in patients with MPN. A nested case-control study found that the occurrence of arterial thrombosis was independently linked to a higher incidence of secondary cancers, particularly among younger patients with MPNs. This correlation underscores the complex interplay between chronic inflammation induced by MPNs and the risk factors for both cardiovascular disease and cancer.

“We believe that arterial, and possibly venous thrombosis occurring during follow-up should be considered in the context of long-term occurring outcomes, including an increased incidence of solid tumors,” concluded the study authors.

Continued research is essential to unravel the underlying mechanisms linking thrombosis with disease progression and secondary malignancies, ultimately improving patient outcomes in this vulnerable population.

Reference

Barbui T, Ghirardi A, Carobbio A, et al. Thrombosis in myeloproliferative neoplasms: a viewpoint on its impact on myelofibrosis, mortality, and solid tumors. Blood Cancer J. 2024;14(1):188. doi:10.1038/s41408-024-01169-6

Carotid Plaque Burden and Neutrophil-Lymphocyte Ratio in Patients with Philadelphia Negative Myeloproliferative Neoplasms and Their Relation to JAK2 V617F Mutation

Posted on April 23, 2024April 23, 2024 by mpn_admin

Mahmoud Gaber, Mohamed Ezeldin, Mustafa Adel Younis, Moamen Abdelfadil Ismail, and Asmaa Ahmed Abdel-baset

Abstract

Background: Philadelphia negative myeloproliferative neoplasms are characterized by clonal myeloid cell proliferation. The JAK2V617F mutation may influence inflammation and atherosclerosis. Neutrophil-Lymphocyte Ratio and carotid plaque burden are markers associated with inflammation and cardiovascular risk, respectively.

This study aimed to investigate the relationship between NLR, carotid plaque burden, and JAK2V617F mutation in PN-MPN patients.

Patients and Methods: A retrospective case-control study included 90 PN-MPN patients and 60 controls. Data on demographics, comorbidities, thrombosis, laboratory parameters, carotid plaque burden, and JAK2V617F mutation status were collected.

Results: Age, gender distribution, smoking status, and comorbidities did not significantly differ between PN-MPN patients and controls. Thrombosis incidence in PN-MPN patients did not significantly differ from controls. Carotid plaque burden and NLR were significantly higher in PN-MPN patients compared to controls (p=0.024 and p<0.001, respectively). Majority of PN-MPN patients (78.9%) had positive JAK2V617F mutation status. NLR was significantly higher in PN-MPN patients with positive JAK2V617F mutation compared to negative (p=0.001). There was a significant difference in thrombosis incidence between patients with positive and negative JAK2V617F mutation status.

Conclusion: The study identified a significant link between higher N/L ratios and the JAK2V617F mutation in patients with PN-MPNs, proposing the N/L ratio as a potential marker for disease activity or mutation status. Despite observing a higher incidence of thrombosis in MPN patients and increased carotid plaque in PN-MPN patients compared to controls, no significant correlation was found between these cardiovascular risk markers and the JAK2V617F mutation status, suggesting other factors influence thrombosis risk in these patients.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence

Posted on February 26, 2024February 26, 2024 by mpn_admin

Laura F. Mendez Luque1,2, Julio Avelar-Barragan3, Hellen Nguyen1, Jenny Nguyen1, Eli M. Soyfer1, Jiarui Liu1, Jane H. Chen1, Nitya Mehrotra1, Xin (Helen) Huang1, Heidi E. Kosiorek4, Amylou Dueck4, Alexander Himstead1, Elena Heide1, Melinda Lem1, Kenza El Alaoui1, Eduard Mas1, Robyn M. Scherber5, Ruben A. Mesa6, Katrine L. Whiteson3, Andrew Odegaard1, Angela G. Fleischman1

ABSTRACT

Purpose: Chronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low- risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients.

Identification of Novel Risk Variants of Inflammatory Factors Related to Myeloproliferative Neoplasm: A Bidirectional Mendelian Randomization Study

Posted on February 19, 2024February 19, 2024 by mpn_admin

Yang Li, Ting Sun, Jia Chen, Lei Zhang

Abstract

Epidemiological and experimental evidence has linked chronic inflammation to the etiology of myeloproliferative neoplasm (MPN). However, it remains unclear whether genetic associations with specific inflammatory biomarkers are causal or due to bias. This study aimed to assess the effect of C-reactive protein (CRP) and systemic inflammatory regulators on MPN within a bidirectional Mendelian randomization design. Genetic associations with MPN were derived from a publicly available genome-wide association study (GWAS) comprising 1,086 cases and 407,155 controls of European ancestry. Additionally, data on inflammation were extracted from two GWASs focusing on CRP and cytokines. The causal relationships between exposure and outcome were explored using the inverse variance weighted (IVW) method. To confirm the final results, multiple sensitivity analyses, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were simultaneously employed. Our results suggest that lower levels of macrophage-migration inhibitory factor (IVW estimate odds ratio [OR IVW] per SD genetic cytokines change: 0.641; 95% confidence interval [CI]: 0.427–0.964; p = 0.032) and higher levels of interleukin-2 receptor α (lL2Rα, 1.377, 95% CI: 1.006–1.883; p = 0.046) are associated with an increased risk of MPN. Genetically predicted MPN is related to increased levels of RANTES (IVW estimate β: 0.043, 95% CI: 0.002–0.084; p = 0.039) and interleukin-10 (IVW estimate β: 0.030, 95% CI: 0.001–0.060; p = 0.041). This study provides evidence for a causal relationship between CRP, systemic inflammatory regulators, and MPN, and new insights into the etiology, prevention, and prognosis of MPN.