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Myeloproliferative neoplasms are characterized by the neoplastic transformation of hematopoietic stem cells and the associated hyperproliferation of myeloid cell lineages, such as granulopoiesis, erythropoiesis, or megakaryopoiesis. These diseases follow a chronic, protracted course and can develop during the aging process against a background of clonal hematopoiesis. The peak incidence of myeloproliferative neoplasms occurs between the ages of 65 and 75. Myeloproliferative neoplasms are among the most common reasons for oncology consultations, and given demographic trends in Europe, a further increase in newly diagnosed cases is expected in the coming decades. The following overview focuses on the three classic BCR::ABL1-negative myeloproliferative neoplasms-polycythemia vera, essential thromcythemia, and primary myelofibrosis-and addresses their epidemiology, clinical characteristics, diagnosis, prognosis, and treatment options.
Polycythemia vera (PV) is a clonal hematopoietic stem cell disorder resulting in overproduction of erythrocytes. Although interferon alfa (IFN-α) has shown therapeutic efficacy in PV and other myeloproliferative neoplasms (MPN), its precise mechanism of action remains poorly understood. In this study, we identify natural killer (NK) cells as primary immune effectors responsive to IFN-α treatment in PV essential for disease control in vivo. Using a transgenic mouse model of PV, we demonstrate that IFN-α induces the expansion of CD27+ NK cells in the bone marrow. In patients with PV or essential thrombocythemia undergoing IFN-α therapy, the frequency of CD56bright NK cells is increased and correlates with the molecular response. Depletion of NK cells abrogated the therapeutic effects of IFN-α. In vitro experiments demonstrate that NK cells preferentially killed Jak2VF mutant hematopoietic stem and progenitor cells in a tumor necrosis factor-α–dependent manner and independent of IFN-γ or NKG2D. Notably, PV mice depleted of NK cells or lacking type-I interferon receptor on NK cells showed accelerated disease progression in the absence of exogenous IFN-α. This suggests that direct sensing of basal levels of type-I interferons by NK cells is essential for attenuating disease progression, emphasizing a critical role for NK cells in immune surveillance of MPN. These findings offer new insights into type-I interferon-mediated immune modulation in MPN and highlight the potential of NK cell activation to improve therapeutic outcomes.
Iron deficiency assessment in myeloproliferative neoplasms is complicated by chronic inflammation, disease-related anemia, and treatment-induced changes in iron handling. We retrospectively analyzed 445 patients with MPN, including 158 with polycythemia vera, 97 with essential thrombocythemia, 44 with prefibrotic primary myelofibrosis, 127 with overt myelofibrosis, and 19 with MPN-unclassifiable, and compared conventional iron parameters with a population-based SHIP cohort of 4420 participants. ZPP was measured in the MPN cohort using quantitative fluorescence spectroscopy. Compared with SHIP, MPN patients had lower hemoglobin and higher ferritin, and the physiological positive correlation between ferritin and hemoglobin observed in SHIP was reversed in MPN patients, with R = 0.27, 95% CI 0.24 to 0.30, p < 0.001 in SHIP versus R = - 0.45, 95% CI - 0.52 to - 0.36, p < 0.001 in MPN. Median ZPP in the MPN cohort was 43.0 µmol/mol heme, with 123 of 445 patients (27.6%) showing ZPP values > 65 µmol/mol heme and 59 of 445 patients (13.3%) showing values > 100 µmol/mol heme. ZPP differed significantly between MPN entities, with median values of 35.0 µmol/mol heme in ET, 49.4 µmol/mol heme in PV, 36.5 µmol/mol heme in pre-PMF, 54.7 µmol/mol heme in overt MF, and 46.0 µmol/mol heme in MPN-U (p < 0.001). ZPP correlated inversely with hemoglobin in MPN patients (R = - 0.26, 95% CI - 0.35 to - 0.16, p < 0.001), whereas its association with ferritin was weak (R = - 0.10, 95% CI - 0.20 to - 0.00, p = 0.045). Among 80 patients with CTCAE grade ≥ 2 anemia, 58 (73%) had ZPP values above the upper limit of normal. In exploratory multivariable analysis, PV, overt MF, and phlebotomy were independently associated with higher ZPP, whereas CRP and time from diagnosis were not. In JAK2-mutated PV versus ET, ZPP was significantly higher in PV (48.5 versus 37.5 µmol/mol heme, p = 0.010), complementing lower transferrin saturation and higher JAK2 variant allele frequency. These data indicate that ZPP provides a functional readout of iron-restricted heme synthesis in MPN, adds information beyond ferritin and transferrin saturation, and may refine diagnostic reassessment and therapeutic monitoring, particularly in PV and overt MF.
Pharmacologic targeting of murine double minute 2 (MDM2) represents one of the most compelling strategies for therapeutic reactivation of wild-type p53 in hematologic malignancies. The MDM2-p53 autoregulatory loop is a central regulator of cellular stress responses, and in myeloid neoplasms-including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN)-p53 is frequently retained but functionally suppressed through MDM2 overexpression and oncogenic signaling, notably via JAK-STAT activation. Over the past decade, successive generations of MDM2 inhibitors have translated structural and mechanistic insights into clinical investigation, yielding critical lessons regarding dosing paradigms, hematologic toxicity, biomarker-driven patient selection, and mechanisms of resistance, including TP53-mutant clonal selection. While early phase III trials in AML were negative, recent studies in myelofibrosis demonstrate clinically meaningful spleen, symptom, and molecular responses, supporting disease-modifying potential in TP53-wild-type settings. Adaptive platform designs and rational combinations with JAK inhibitors, BCL-2 antagonists, and interferons have further refined therapeutic strategies. Emerging MDM2 degraders and next-generation agents aim to overcome feedback limitations and improve therapeutic index. This review integrates mechanistic foundations, clinical development, resistance biology, and future directions, highlighting how decades of basic science have reshaped p53 reactivation into a precision therapeutic paradigm in myeloid disease.
Most myelofibrosis (MF) patients treated with ruxolitinib fail to achieve optimal response (i.e., spleen volume reduction ≥35% [SVR35] and improvement in total symptom score ≥50% [TSS50], and instead experience suboptimal reductions in spleen volume and constitutional symptoms. Maximizing SVR and TSS is critical for MF patients, as both are associated with improved quality of life (QoL) and overall survival (OS). Navtemadlin is a potent, selective, oral MDM2 inhibitor that restores p53 activity, inducing apoptosis of malignant TP53 wild-type (TP53WT) CD34+ MF progenitor cells. In vitro and clinical data demonstrated navtemadlin's synergy with ruxolitinib and disease-modifying potential. POIESIS is a global, randomized, double-blind phase III trial evaluating navtemadlin versus placebo as add-on to ruxolitinib in JAK inhibitor-naïve TP53WT MF patients with suboptimal response to ruxolitinib. The study includes a ruxolitinib monotherapy run-in period, followed by randomization of suboptimal responders to add-on navtemadlin or placebo to their stable ruxolitinib dose. Study objectives are to isolate the contribution of add-on navtemadlin by assessing SVR and TSS 24-weeks after randomization from the pre-randomization baseline and to demonstrate that this contribution is clinically meaningful using established SVR and TSS endpoints from the pre-ruxolitinib treatment baseline. Secondary endpoints include progression-free survival, leukemia-free survival, and OS.
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.
The prefibrotic phase of primary myelofibrosis (pre-PMF) represents a distinct subentity within the spectrum of myeloproliferative neoplasms (MPNs), recognized by the World Health Organization (WHO) and the International Consensus Classification (ICC). Pre-PMF is characterized by unique morphological, clinical, and molecular features, distinguishing it from essential thrombocythemia (ET) and overt myelofibrosis (overt-PMF). The diagnostic process for pre-PMF relies on bone marrow histology, identification of molecular mutations and exclusion of other myeloid neoplasms. Misclassification remains a significant challenge due to overlapping phenotypes and the heterogeneity of clinical presentations, which range from asymptomatic cases to severe cytopenias and a high thrombotic risk. Management strategies for pre-PMF focus on mitigating symptom burden, reducing thromboembolic events, and preventing disease progression. Low-risk patients often benefit from observational approaches or low-dose aspirin, while cytoreductive therapies, such as hydroxyurea or interferon-alpha, are utilized in symptomatic or high-risk cases. JAK inhibitors like ruxolitinib have shown promise in addressing splenomegaly and systemic symptoms, although their role in pre-PMF requires further investigation. Advances in artificial intelligence are enhancing diagnostic precision by refining bone marrow histopathological analysis, paving the way for more accurate disease classification and tailored therapeutic strategies. This position paper integrates insights from a German expert panel discussion, underscoring the need for interdisciplinary collaboration, adherence to updated WHO/ICC diagnostic criteria, and personalized treatment approaches. By addressing diagnostic challenges and therapeutic nuances, it seeks to improve outcomes and quality of life for patients navigating the complexities of pre-PMF.
Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system and in haematopoietic cancers. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2-ERK signalling and the maintenance of JAK2V617F malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2.
Research on myeloid neoplasms, a field that has been driving scientific advances in cancer for over 50 years, has yielded many discoveries that have fundamentally reshaped our understanding of cancer biology. These insights, often the product of leukemia research, have been instrumental in developing more mechanism-based treatments in the early 2000s. Recognizing epigenetic dysregulation as a common disease mechanism in myeloid cancers has been groundbreaking regarding recent treatment developments that exploit chromatin-based oncogenic mechanisms. In the case of acute myeloid leukemia (AML), sequencing studies aimed at assessing the complement of genetic alterations demonstrated that more than 60% of AML cases harbored disease-driving mutations in epigenetic regulators. This high prevalence underscores the importance of epigenetic dysregulation in AML pathogenesis. Chromatin regulators commonly control disease-specific transcriptional programs, making them attractive therapeutic targets to manipulate neoplastic gene expression programs, particularly in myeloid neoplasms. Several drugs targeting epigenetic mechanisms and exploiting myeloid disease-specific dependencies have recently been approved for treating myeloid neoplasms. Many additional drugs are currently being investigated in clinical trials, and numerous new compound developments are being studied in preclinical studies. This manuscript will review (1) chromatin-based disease mechanisms, such as DNA methylation, chromatin regulatory complexes, and histone modifications, currently investigated for therapeutic exploitation in myeloid malignancies, and (2) therapeutic developments already approved or investigated for treating these diseases.
Persistence of JAK2-mutated clones that may undergo clonal evolution and malignant transformation remains a challenge in myeloproliferative neoplasms (MPN), Novel therapeutic approaches to attenuate clonal evolution and progression to blast-phase are therefore urgently needed. LSD1 (KDM1A) inhibitors reduce symptoms and clonal burden in MPN, but whether these compounds may be effective in advanced disease stages remained so far elusive. Using a chromatin-focused CRISPR-Cas9 screen, we identified the histone methyltransferase DOT1L as a synthetic lethal target under pharmacologic LSD1 inhibition. DOT1L knockout impaired cellular fitness, reduced proliferation, and prolonged survival in xenografts. Furthermore, genetic inactivation of DOT1L increased LSD1 inhibitor sensitivity up to 100-fold resulting in cell cycle arrest and apoptosis induction in TP53 mutant blast-phase MPN. Mechanistically, we have identified a novel, non-canonical function of DOT1L which co-occupied LSD1-bound enhancers and contributed to the repression of transcriptional programs independent of its enzymatic activity. DOT1L loss cooperated with LSD1 inhibitors to activate tumor suppressive programs, while pharmacologic inhibition of DOT1Ls catalytic activity failed to elicit comparable effects. These findings indicate that leveraging DOT1L targeting via protein degradation or RNA interference, rather than conventional enzymatic inhibition, could enhance the therapeutic efficacy of LSD1 inhibitors in blast-phase MPN.
Classical myeloproliferative neoplasms (MPN) are clonal stem cell disorders characterized by driver mutations that affect the constitutive activation of JAK-signaling. Mutations additional to an MPN-driver occur in a large number of patients and have been shown be associated with disease presentation and progression. In this review, we outline the current hypotheses regarding how clonal evolution in MPN is thought to occur and the functional mechanisms as to how concomitant somatic mutations (i.e., mutations in genes other than the 'driver' genes) contribute to disease progression. We discuss the definitions of high molecular risk MPN, provide an overview of how concomitant mutations influence the clinical management of MPN and suggest how the rapidly developing genetic risk stratification can be utilized to improve clinical outcomes.
BCR::ABL1-negative myeloproliferative neoplasms are chronic diseases characterized by high symptom burden due to systemic inflammation. Treatment objectives include cytoreduction and alleviation of symptoms. Besides standard therapies, complementary and alternative medicine (CAM) methods are frequently used and requested by cancer patients. Aim of this study was to assess the interest in and use of CAM by patients diagnosed with MPN and it was conducted as a patient-reported, paper-and-pencil-based questionnaire.
166 patients with MPN were included, 72 (43.4%) male and 94 (56.6%) female. Median age was 65.0 years. Diagnoses included ET 66/166 (39.8%), PV 40/166 (24.1%), MF 51/166 (30.7%) MPN-U 8/166 (4.8%) and SM-AHN 1/166 (0.6%). Overall, more frequent use of CAM was documented in females (59.6%) compared to males (41.7%), p = 0.022. A significant proportion of patients reported on the ingestion of nutritional supplements: 44/163 (26.5%) vitamin D, 26/165 (15.7%) vitamin C, 19/165 (11.4%) zinc, 13/165 (7.8%) secondary plant products, 12/165 (7.2%) selenium, and 19/165 (11.4%) multivitamin preparations. Regarding other CAM-related measures: 5/164 (3.0%) used amygdalin, 4/164 (2.4%) mistletoe therapy, 11/165 (6.6%) acupuncture, 6/165 (3.6%) homeopathy, 11/165 (6.6%) yoga, 10/165 (6%) reported receiving spiritual support, while 3/165 (1.8%) used the services of "healers". A higher rate of CAM use was found among patients with longer disease duration.
Use of CAM was recorded in the majority of patients with MPN. Higher use of CAM-related measures was reported by women and patients with longer disease duration. Patients should be regularly consulted about the use of CAM, its risks should be considered and pointed out, and safe methods should be recommended.
Epigenetic modulators of the histone deacetylase (HDAC) family control key biological processes and are frequently dysregulated in cancer. There is superior activity of HDAC inhibitors (HDACi) in patients with myeloproliferative neoplasms (MPNs) that carry the Janus kinase-2 point mutant JAK2V617F. This constitutively active tyrosine kinase activates signal-transducer-and-activator-of-transcription (STAT) transcription factors to promote cell proliferation and inflammatory processes. We reveal that the inhibition of HDAC1/HDAC2 with the clinically advanced HDACi romidepsin, the experimental HDACi entinostat and MERCK60, and genetic depletion of HDAC1/HDAC2 induce apoptosis and long-term growth arrest of primary and permanent MPN cells in vitro and in vivo. This treatment spares normal hematopoietic stem cells and does not compromise blood cell differentiation. At the molecular level, HDAC1 and HDAC2 control the protein stability of SIAH2 through acetylation. Genetic knockout experiments show that SIAH2 accelerates the proteasomal degradation of JAK2V617F in conjunction with the E2 ubiquitin-conjugating enzyme UBCH8. SIAH2 binds to the surface-exposed SIAH degron motif VLP1002 in the catalytic domain of JAK2V617F. At the functional level, SIAH2 knockout MPN cells are significantly less sensitive to HDACi. Global RNA sequencing verifies that JAK-STAT signaling is a prime target of SIAH2. Moreover, HDAC1 is an adverse prognostic factor in patients with acute myeloid leukemia (n = 150, p = 0.02), being a possible complication of MPNs. These insights reveal a previously unappreciated link between HDAC1/HDAC2 as key molecular targets, the still undefined regulation of cytoplasmic-to-nuclear signaling by HDACs, and how HDACi kill JAK2V617F-positive cells from MPN patients and mice with JAK2V617F in vitro and in vivo.
Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ∼70% of patients discontinue ruxolitinib after ∼5 years, a third of whom report suboptimal splenic response. ADORE was a phase 1b/2 study with an innovative open platform design that assessed the safety, efficacy, and pharmacokinetics of novel compounds in combination with ruxolitinib in patients with MF who had a suboptimal response to ruxolitinib alone. A total of 44 patients were enrolled in part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Most patients were allocated to receive ruxolitinib plus siremadlin (N = 23). The most frequent adverse events with siremadlin were gastrointestinal (nausea and diarrhea) and hematological (thrombocytopenia, anemia, and neutropenia). Siremadlin 30 mg orally once daily on days 1 to 5 of a 28-day cycle was selected as the recommended phase 2 dose. The most robust spleen volume reduction (SVR) at 24 weeks was observed with ruxolitinib plus siremadlin 30 mg. Reductions in percent JAK2V617F allele burden at week 24 were observed, notably in several patients with SVR. An increase in growth differentiation factor 15 protein levels in patients receiving siremadlin demonstrated the on-target modulation of downstream p53 targets. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone.
Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased thromboembolic (TE) risk and hematologic complications. Hydroxyurea (HU) serves as the most frequently used first-line cytoreductive therapy worldwide; however, resistance to HU (HU-RES) develops in a significant subset of patients, leading to increased morbidity and necessitating alternative treatments. This study, part of the PV-AIM project, employed machine learning techniques on real-world evidence (RWE) from the Optum® EHR database containing 82.960 PV patients to identify baseline predictors of HU-RES within the first 6-9 months of therapy. Using a Random Forest model, the study analyzed data from 1850 patients, focusing on laboratory parameters and clinical characteristics. Key predictive markers included red cell distribution width (RDW) and hemoglobin (HGB), showing the strongest association with HU-RES. A synergistic interaction between RDW and HGB was identified, enabling TE risk stratification. This study provides a robust framework for early detection of HU-RES using readily available clinical data, facilitating timely intervention. These findings underscore the importance of personalized treatment approaches in managing PV and highlight the utility of machine learning in enhancing predictive accuracy and clinical outcomes. Based on the results of PV-AIM we initiated an open-label, prospective, single-arm, interventional, phase IV study (HU-F-AIM) evaluating HU-resistance/intolerance. Validation of predictive biomarkers may facilitate identification of patients at risk of HU resistance who may benefit from alternative treatment options, possibly preventing ongoing phlebotomy during HU treatment, a frequent therapeutic choice in high-risk PV associated with early disease progression and increased thromboembolic complications. We propose an updated terminology that differentiates between true molecular resistance and clinical resistance, that may indicate the requirement for alternative therapeutic strategies.
Myeloproliferative neoplasms (MPN) are associated with a variety of symptoms that severely impact patients' quality of life and ability to perform daily activities. Recent studies showed differences in the perception of physician- versus patient-reported symptom burden. However, studies directly comparing patient- and physician-reported ratings are lacking. Here, a retrospective analysis on symptom burden of 3979 MPN patients of the Bioregistry of the German Study Group for MPN was conducted to intra-individually compare physician and patient reports collected at the same time. Cohen's kappa was calculated to assess the degree of agreement between patient and physician reports. Factors influencing baseline symptom severity were identified using linear regression and adjusted Cox models were calculated to investigate the effect of symptom burden on survival. MPN patients had a high symptom burden, which neither decreased over time nor upon cytoreductive therapy. All symptoms were more frequently reported by patients compared to physicians. Agreement remained low and only slightly improved when considering a higher threshold for patient symptom severity. Patients with severe symptom burden had inferior survival compared to patients with less severe symptoms. Assessment of symptom burden in MPN is therefore insufficient and patient-reported outcome tools need to be implemented into clinical routine.