JAK-STAT signaling

Current understanding

Constitutive activation of the JAK2-STAT pathway is the central driver of MPN clonal proliferation. JAK2 V617F is the most common driver mutation across PV, ET, and PMF.

Evidence log

• 2026-10-04 — Momelotinib induces hemoglobin improvement and symptom control in PCM1::JAK2-associated myeloid neoplasm.: Case report of momelotinib producing hemoglobin improvement and symptom control in a PCM1::JAK2 fusion-driven myeloid neoplasm extends dual JAK-STAT/ACVR1 blockade’s clinical footprint to a rare JAK2-rearrangement genotype beyond canonical JAK2V617F. (novelty: 3)
• 2026-10-07 — Aberrant erythrocyte rigidity in JAK2myeloproliferative neoplasms underlies concurrent thrombosis and hemorrhage.: Preclinical evidence extends JAK2V617F pathology to erythrocyte biomechanics, showing JAK-STAT activation during erythropoiesis remodels RBC membrane and cytoskeleton to produce intrinsically rigid cells that impair clot contraction, linking driver-kinase activity to downstream hemostatic phenotype via a non-signaling structural output. (novelty: 5)
• 2026-09-01 — Fibrocytes drive JAK2V617F-mutated myelofibrosis: pitavastatin reverses marrow fibrosis and anemia.: Preclinical study in JAK2V617F MF shows pitavastatin reverses fibrosis and anemia via inhibition of monocyte-derived fibrocytes and TGF-β1, offering a JAK-STAT-independent antifibrotic strategy that acts on a downstream cellular effector rather than the driver kinase. (novelty: 4)
• 2026-09-24 — Selective dependency of CALR-mutant myeloproliferative neoplasms on TYK2 signaling.: Preclinical work refines the JAK-STAT pathway model by showing TYK2 (not JAK2) is the required kinase downstream of mutant CALR–MPL and MPLW515K, whereas JAK2V617F displaces TYK2 from TPOR — implying the ‘JAK’ engaged by each driver mutation is genotype-specific rather than uniformly JAK2. (novelty: 5)
• 2026-09-15 — Type 1 interferon perturbates clonal competition by reshaping human blood development.: Preclinical single-cell data show IFNα induces polarized lymphoid vs inflammatory-myeloid differentiation in human HSCs, with JAK2- and CALR-mutant stem cells resisting the inflammatory-myeloid branch — implicating driver-mediated JAK-STAT/IFN response tuning as a determinant of clonal fitness under IFNα. (novelty: 4)
• 2026-08-13 — Study of Flonoltinib Maleate Tablets in the Treatment of Proliferative Bone Marrow Tumors: Early-phase clinical trial of flonoltinib maleate (highly JAK2-selective dual JAK2/FLT3 inhibitor) in intermediate/high-risk MF, PV, and ET evaluates safety, MTD, PK, and preliminary efficacy, extending JAK-STAT–directed therapy with a preclinically higher-selectivity, lower-toxicity agent versus ruxolitinib/fedratinib. (novelty: 3)
• 2026-07-15 — Phase I/II Clinical Trial of Axatilimab, a CSF1R Monoclonal Antibody, in Combination With Ruxolitinib as Therapy for Patients With Myelofibrosis (MF) and Chronic Myelomonocytic Leukemia (CMML): cross-connection with csf1r-macrophage-signaling-mpn: Trial pairs CSF1R blockade with ruxolitinib, explicitly testing whether combined macrophage/monocyte depletion and JAK-STAT inhibition cooperate in MF and CMML. (novelty: 3)
• 2026-07-16 — An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis on Concomitant JAK2 Inhibitor Therapy and Who Require Red Blood Cell Transfusions: cross-connection with tgf-beta-superfamily-signaling-mpn: Trial couples TGF-β superfamily ligand trapping (luspatercept) with JAK2 inhibitor backbone therapy, operationalizing a combined JAK-STAT + TGF-β/SMAD blockade strategy for MF-associated anemia. (novelty: 3)
• 2026-08-01 — Type II JAK2 Inhibitor Gets Off to a Strong Start.: Phase I clinical signal for AJ1-11095 (type II inactive-conformation JAK2 inhibitor) reports responses that may exceed those achievable with approved type I JAK2 inhibitors, supporting the therapeutic relevance of conformational selectivity within JAK-STAT-directed pharmacology. (novelty: 4)
• 2026-06-10 — Ropeginterferon alfa-2b-njft treatment in essential thrombocythemia across different driver mutations: results from a North American, single-arm, multicentre study (EXCEED-ET).: EXCEED-ET shows ropeginterferon alfa-2b produces hematologic and molecular responses across all three canonical JAK-STAT-activating driver genotypes (JAK2, CALR, MPL) in North American ET, reinforcing IFN-α as a driver-agnostic suppressor of JAK-STAT-activated clones in ET. (novelty: 3)
• 2025-06-26 — Efficacy and Safety of Ropeginterferon Alfa-2b in Low-Risk Polycythemia Vera.: Prospective trial in low-risk PV shows ropeginterferon alfa-2b reduces JAK2V617F allele burden while achieving complete hematologic response, reinforcing IFN-α–driven suppression of the JAK-STAT-activating mutant clone in the earlier-stage PV population. (novelty: 3)
• 2026-08-01 — Ropeginterferon alfa-2b in Polycythemia Vera: A systematic review and meta-analysis.: Meta-analysis of 3 RCTs (n=522) finds ropeginterferon alfa-2b significantly reduces JAK2V617F allele burden versus phlebotomy alone but not versus hydroxyurea, suggesting both cytoreductive agents suppress the JAK-STAT-activating mutant clone at comparable magnitude in PV. (novelty: 3)
• 2026-08-06 — Collagen Turnover Is Associated with Disease Severity, Bone Marrow Fibrosis, and theVariant Allele Frequency in Myeloproliferative Neoplasms.: Serum PRO-C3 collagen turnover correlates with driver mutation VAF in MPN, linking JAK-STAT clonal burden to systemic ECM remodeling activity. (novelty: 3)
• 2026-06-02 — Selinexor Plus Ruxolitinib in Janus Kinase Inhibitor-Naïve Myelofibrosis: Phase III SENTRY Trial.: Phase III SENTRY provides the first large randomized late-stage evidence that layering XPO1 inhibition on catalytic JAK-STAT blockade produces additive spleen responses and an early OS signal in JAKi-naïve MF, though without improvement in symptom burden — reinforcing that JAK-STAT inhibition alone under-treats key MF axes but that combination hematologic toxicity is additive. (novelty: 3)
• 2026-07-23 — Complete Hematological Response Coupled with Molecular Response in Polycythemia Vera Treatment with Ropeginterferon Alfa-2b.: Observational PV series showing early (mean 4.15-month) concurrent CHR and JAK2 VAF decline under slow-titrated ropeginterferon alfa-2b indirectly supports that IFN-α–driven suppression of the JAK-STAT-activating mutant clone can be detected on a short timescale, complementing the HIDAT dose-intensity findings. (novelty: 3)
• 2026-07-14 — Targeting nuclear export and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling in myelofibrosis: A novel combinatorial strategy that impacts intrinsic and microenvironment-related pathways.: Preclinical combinatorial data indicate dual XPO1/JAK2 blockade (selinexor + ruxolitinib) suppresses JAK/STAT signaling more deeply than ruxolitinib alone and retains activity in ruxolitinib-resistant MF models, supporting nuclear export as a mechanistically complementary axis to catalytic JAK inhibition. (novelty: 3)
• 2026-08-18 — Immune and cytokine landscape differs between cytopenic and proliferative phenotypes in primary myelofibrosis.: Cytopenic vs proliferative PMF stratification suggests NF-κB inflammatory activation (rather than JAK-STAT proliferative drive) dominates the cytopenic phenotype, implying JAK-STAT output alone does not account for phenotypic divergence in PMF. (novelty: 3)
• 2026-08-01 — Inflammatory Network Architecture Across Bone Marrow Failure: An Immune-Genetic Continuum.: Integrative BMF review casts JAK-STAT as one of two dominant transcriptional hubs (with NF-κB) transducing the conserved TNF-α/IFN-γ/IL-6 cytokine core across bone marrow failure syndromes including MPN/MF. (novelty: 3)
• 2026-09-03 — Targeting Thrombopoietin/MPL Signaling to Mitigate JAK2V617F-Driven Cardiac Microvascular Disease.: JAK2V617F-mutant hematopoiesis drives cardiac microvascular disease under cardiometabolic stress through upregulated endocardial thrombopoietin/MPL signaling — extending JAK2V617F’s non-hematopoietic footprint to endocardial endothelium and offering anti-MPL antibody rescue. (novelty: 4)
• 2026-08-20 — Mutational landscape of classical myeloproliferative neoplasms in the Western Cape Province, South Africa.: Western Cape South African tertiary-hospital MPN cohort found JAK2 p.V617F was the predominant driver mutation, consistent with JAK-STAT activation as the central pathogenic axis across geographically diverse populations. (novelty: 3)
• 2026-07-23 — Hyperviscosity encephalopathy in suspected polycythemia vera at high altitude: a case report.: Case report underscores that in high-altitude polycythemia the JAK2 mutational assay (paired with serum EPO) is the pivotal test distinguishing primary JAK-STAT-driven PV from EPO-mediated secondary erythrocytosis, since the two share an identical erythrocytotic phenotype but diverge mechanistically at pathway activation. (novelty: 3)
• 2026-07-17 — Cross-study analyses of the ropeginterferon alfa-2b effect on phlebotomy in low- and high-risk patients with polycythemia vera.: Cross-study analysis of ropeginterferon alfa-2b in PV reports dose-intensified (HIDAT) titration achieves deeper JAK2V617F allele-burden reduction than slow titration, indirectly supporting that pharmacologic exposure to IFN-α scales with suppression of the JAK-STAT-driving mutant clone. (novelty: 3)
• 2026-07-01 — Phase I Trial of Pacritinib in Combination With Venetoclax and Azacitidine for the Treatment of Accelerated and Blast Phase Myeloproliferative Neoplasms: Phase I trial of pacritinib (JAK2/FLT3/IRAK1) + venetoclax + azacitidine in accelerated/blast-phase MPN extends JAK-STAT blockade combinations into a triple-pathway strategy (JAK-STAT + BCL-2 apoptotic + HMA epigenetic) for advanced-phase disease. (novelty: 4)
• 2026-07-02 — A Study to Evaluate Single Agent Selinexor Versus Physician’s Choice in Participants With Previously Treated Myelofibrosis: Randomized Phase 2 of selinexor monotherapy versus physician’s choice in JAKi-pretreated MF tests whether XPO1 blockade alone can substitute for continued JAK-STAT-directed therapy after ≥6 months of JAK1/2 inhibition. (novelty: 3)
• 2026-07-01 — DDX5: a versatile RNA helicase in cancer and cell fate determination-linking c-Myc and JAK2 V617F signalling to emerging therapeutics.: Review posits DDX5 as a helicase-independent scaffolding co-activator indispensable for JAK2 V617F-driven MPN transformation, coupling JAK-STAT output to a c-Myc positive feedback loop and nominating the DDX5 degrader FL118 as a novel therapeutic strategy downstream of catalytic JAK inhibition. (novelty: 4)
• 2025-11-20 — Splenic Artery Aneurysm Associated with Myelofibrosis Managed by Coil Embolization.: Case report of a JAK2 V617F-positive secondary MF patient with splenic artery aneurysm where ruxolitinib-induced splenomegaly reduction improved splanchnic hemodynamics enough to permit safe spleen-preserving coil embolization, illustrating JAK-STAT blockade’s utility as a peri-procedural bridge for MF-associated vascular complications. (novelty: 3)
• 2026-04-27 — JAK Inhibitor-Induced Improvement of IgA Nephropathy in a Patient With Polycythemia Vera: A Case Report.: Case report of ruxolitinib in a PV patient with concurrent IgA nephropathy showing reduced proteinuria and stabilized renal function, extending JAK-STAT blockade’s clinical footprint to MPN-associated glomerular disease via presumed IL-6/IL-11 suppression. (novelty: 4)
• 2026-07-03 — Multidisciplinary Characterization of Rare MPL Y591 and R592 Variants in Myeloid Disorders: From Clinical Correlation and Literature-Based Evidence to In Silico Predictors and Structural Bioinformatics.: In silico and structural analysis of rare MPL Y591/R592 variants proposes a hypersensitivity mechanism whereby loss of a phosphorylation-dependent docking site and YXXφ motif at the MPL cytoplasmic tail amplifies TPO-induced JAK-STAT signaling without constitutive activation, illustrating a receptor-tuning route to pathway activation distinct from JAK2V617F or W515. (novelty: 4)
• 2026 (rece — Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications: Review consolidates the mutant CALR–MPL tetramer model as the upstream structural event triggering constitutive JAK-STAT activation in CALR-mutant ET/MF, complementing JAK2V617F as a parallel route to pathway activation. (novelty: 3)
• May 1, 202 — Myelofibrosis (MF) in 2026: Matching Therapy to the Dominant Clinical Problem: 2026 MF review reinforces pelabresib + ruxolitinib (MANIFEST-2) as a phase 3-validated BET+JAK-STAT combination for JAKi-naïve intermediate-1 or higher-risk MF, supporting layered transcriptional + JAK-STAT blockade as a frontline strategy. (novelty: 3)
• 2025-10-30 — Effective Treatment with Ruxolitinib and Ropeginterferon Alfa-2b for Refractory TAFRO-like Syndrome.: Case report describes successful use of ruxolitinib + ropeginterferon alfa-2b combination to resolve refractory TAFRO-like syndrome in a JAK2 V617F PV patient, suggesting dual JAK-STAT blockade plus IFN-α-mediated clonal suppression can quell a hyperinflammatory MPN complication. (novelty: 3)
• 2026-06-13 — Lilly to present initial clinical data for first-in-class type II JAK2 inhibitor in patients with previously treated myelofibrosis at the 2026 EHA Annual Meeting: Initial clinical data for AJ1-11095 (first-in-class type II JAK2 inhibitor) in previously treated MF show safety and spleen volume reduction activity across JAK2, MPL, and CALR type 1/2 mutation subgroups, providing first in-patient evidence that inactive-conformation JAK2 binding can suppress JAK-STAT-driven disease after type I JAKi failure. (novelty: 4)
• 2026-06-10 — Ropeginterferon for High Risk JAK2 Clonal Hematopoiesis: Ropeginterferon alfa-2b is being trialed in pre-MPN JAK2-mutant clonal hematopoiesis, testing whether IFN-α-mediated suppression of JAK-STAT-activated clones is feasible before overt disease emerges. (novelty: 4)
• 2026-06-08 — Selinexor in Myelofibrosis Refractory or Intolerant to JAK1/2 Inhibitors: Phase II trial of selinexor monotherapy in JAKi-refractory/intolerant MF probes whether XPO1 nuclear export blockade can suppress disease in patients where pharmacologic JAK-STAT inhibition has failed, extending the post-JAKi-failure portfolio into single-agent orthogonal-mechanism territory. (novelty: 3)
• 2026-06-11 — Elotuzumab for the Treatment of JAK2-Mutated Myelofibrosis: Phase II trial of elotuzumab (anti-SLAMF7 mAb) in JAK2-mutated myelofibrosis introduces a SLAMF7-directed immunotherapy axis as an entirely orthogonal strategy to catalytic JAK inhibition for JAK-STAT-driven MPN, expanding the immunotherapy portfolio beyond PD-1 checkpoint blockade and NK/TCR approaches. (novelty: 4)
• 2026-03-20 — Association between JAK2 Mutations and Thoracic Aortic Aneurysms in Myeloproliferative Neoplasms: Scoping review links JAK2 mutations in MPN to thoracic aortic aneurysm, extending the clinical footprint of JAK-STAT-driven disease from hematopoietic and thrombotic phenotypes into large-vessel structural vasculopathy. (novelty: 4)
• 2026-06-05 — The impact of novel bet inhibitors on the treatment armamentarium of Myelofibrosis.: Review of BET inhibitors in MF argues that pelabresib and related agents complement JAK-STAT blockade by suppressing parallel inflammatory/fibrotic/proliferative transcriptional programs that ruxolitinib leaves intact, reinforcing the rationale for BET+JAKi combinations. (novelty: 3)
• 2026-06-01 — Cytokine receptor and JAK/STAT pathway mutations in acute myeloid leukemia: Prevalence and clinical impact.: Large AML cohort (n=971) shows cytokine receptor/JAK-STAT pathway mutations are uncommon (~10% combined) in AML, and JAK2-mutated de novo AML’s poor outcomes are largely driven by co-occurring high-risk features rather than JAK-STAT activation per se — arguing that JAK2 mutation alone is insufficient to confer leukemic aggressiveness outside the MPN-transformation context. (novelty: 3)
• 2026-06-02 — Genomic insights transform diagnosis, prognosis, and therapy in BCR::ABL1-negative myeloproliferative neoplasms.: Review situates JAK-STAT pathway-level cytoreduction as insufficient on its own, arguing that genomically-informed, mutation-selective therapies and clone-tracking biomarkers should layer on top of catalytic JAK inhibition to deliver disease modification. (novelty: 3)
• 2026-05-26 — JAK2V617F Mutated Endothelium Has a Stem Cell Potential in Primary Myelofibrosis: a New Disease Ontogenesis for Chronic Myeloproliferative Disorders: Preclinical work extends the relevant compartment of JAK2V617F mutation beyond HSCs to mature endothelial cells, where the mutation may unlock hemogenic stem-cell-like multilineage potential — implying JAK-STAT activation in endothelium contributes to disease initiation, not just hematopoietic propagation. (novelty: 5)
• December 6 — Prelude Therapeutics Presents Data at 2025 ASH Annual Meeting from its Myeloproliferative Neoplasm Programs: Preclinical ASH 2025 data on PRT12396 indicate JH2-directed mutant-selective inhibition can suppress JAK2V617F-driven signaling more potently than ruxolitinib while preserving wild-type JAK2 cytokine signaling, supporting a wider therapeutic window for selective JAK-STAT blockade. (novelty: 4)
• March 24, — ASH 2025: Myelofibrosis Roundup: ASH 2025 Phase 1 INCA033989 readout showed clinical activity (spleen, anemia, symptoms) in JAKi-resistant/intolerant MF, suggesting upstream mutant CALR–MPL blockade can suppress JAK-STAT-driven disease where catalytic JAK inhibition has failed. (novelty: 5)
• 2026-05-19 — TGR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea: Phase 1 trial of TGR-1202 (PI3Kδ inhibitor) + ruxolitinib spans PV (HU-resistant), PMF, PPV-MF, PET-MF, and MDS/MPN, adding another PI3Kδ partner to the growing portfolio of agents layered onto JAK-STAT blockade and broadening dual JAK-STAT/PI3K-AKT inhibition beyond the MF setting. (novelty: 3)
• February 3 — Prelude Therapeutics Receives FDA Clearance of Investigational New Drug Application (IND) for PRT12396, a Mutant-selective JAK2V617F Inhibitor: FDA IND clearance of PRT12396, a mutant-selective JAK2V617F inhibitor targeting the JH2 pseudokinase domain (Phase 1 expected Q2 2026), introduces a mechanistically distinct allosteric/mutant-selective approach to JAK-STAT blockade beyond catalytic-site pan-JAK inhibitors and Type II conformational JAK2 inhibitors. (novelty: 4)
• May 12, 20 — CALR Mutation–Directed Agents and Targeted Therapies Represent Key Research Avenue in MPN Management: Review situates JAK2-directed precision therapy alongside CALR- and MPL-directed agents and novel partners (selinexor, pelabresib, imetelstat) as the converging precision-medicine landscape for JAK-STAT-driven MPN. (novelty: 3)
• 2026-05-10 — Scalable genotyping in fixed transcriptomes resolves clonal heterogeneity via single-cell sequencing: Single-cell multi-omic profiling (GIFT) shows JAK2V617F allele dosage produces a graded, not binary, activation signature in HSCs, with mutant allele dose scaling an interferon-associated transcriptional program — refining JAK-STAT activation as a continuous dose-dependent state. (novelty: 5)
• 2026-02-25 — Evaluation of the Pathobiology of CALR-mutated MPN Cells: Differential thrombotic phenotype between CALR- and JAK2-driven MPN cells suggests JAK-STAT activation mode (mutant CALR–MPL vs. JAK2 V617F) shapes downstream prothrombotic biology distinctly, despite shared pathway engagement. (novelty: 3)
• 2026-04-14 — A Study of JNJ-88549968 for the Treatment of Calreticulin (CALR)-Mutated Myeloproliferative Neoplasms: cross-connection with calr-mutations: JNJ-88549968 combination arms with JAK inhibitors (ruxolitinib, momelotinib) propose dual targeting of mutant CALR and downstream JAK-STAT signaling, linking CALR-specific therapy to JAK pathway blockade. (novelty: 4)
• 2026-04-14 — Mechanism of Action of Interferon in the Treatment of Myeloproliferative Neoplasms: Mechanistic review highlights that IFN-α achieves molecular responses preferentially in JAK2V617F-mutant MPN, framing IFN-α-mediated clonal suppression as mechanistically distinct from but complementary to pharmacologic JAK-STAT inhibition. (novelty: 3)
• 2026-02-05 — A Study of Elritercept Alone or Together With Ruxolitinib in Adults With Myelofibrosis: Elritercept ± ruxolitinib early-phase MF trial adds a TGF-β superfamily ligand trap to the growing portfolio of anemia-targeted partners (luspatercept, momelotinib’s ACVR1 component) layered onto JAK-STAT blockade. (novelty: 4)
• 2026-04-03 — A Study of Ruxolitinib in Combination With Ulixertinib in People With Myelofibrosis: Phase I/II trial of ruxolitinib + ulixertinib (ERK1/2 inhibitor) adds ERK/MAPK pathway blockade to the growing portfolio of add-on partners (BCL-2/BCL-XL, BET, MDM2, XPO1, PI3K, S100A9, LSD1) layered onto JAK-STAT inhibition, specifically targeting a downstream MAPK escape route from JAK inhibition. (novelty: 4)
• 2026-03-30 — A Study to Assess a PI3Kδ Inhibitor (IOA-244) in Patients With Metastatic Cancers: IOA-244 (selective PI3Kδ inhibitor) ± ruxolitinib trial in PMF adds a second PI3Kδ-selective agent (alongside roginolisib) to the growing portfolio of add-on partners layered onto JAK-STAT blockade. (novelty: 4)
• 2026-04-08 — A Clinical Trial of Flonoltinib Maleate Tablets in the Treatment of JAK Inhibitor Refractory/Relapsed/Intolerant Patients With Medium to High Risk Myelofibrosis: Single-arm open-label multicenter trial of flonoltinib maleate in ~64 JAK inhibitor refractory/relapsed/intolerant intermediate-to-high-risk MF patients extends evaluation of this multi-kinase JAK2/FLT3/CDK6 inhibitor specifically into the post-JAKi-failure setting, complementing the FMF-02 head-to-head and prior flonoltinib MF/PV protocols. (novelty: 4)
• 2026-02-20 — Bomedemstat (IMG-7289) in Combination With Momelotinib in Patients With Myelofibrosis: Phase 2 trial layers bomedemstat (LSD1 inhibitor) onto momelotinib in MF patients with suboptimal monotherapy response or baseline cytopenias, adding LSD1-mediated epigenetic reprogramming to the growing portfolio of add-on partners potentiating JAK-STAT blockade and specifically pairing with momelotinib’s anemia-friendly profile. (novelty: 4)
• April 28, — Fedratinib Shows Promise in MDS/MPN Overlap Syndromes and CNL: Phase 2 trial of fedratinib in MDS/MPN overlap syndromes (MDS/MPN-U, MDS/MPN-RS-T, aCML) and chronic neutrophilic leukemia shows promising efficacy and manageable safety, extending JAK2-selective inhibition beyond classical Ph-negative MPNs into rare myeloid neoplasms with shared JAK-STAT activation. (novelty: 4)
• April 27, — Lilly to Acquire Ajax Therapeutics for Next-Generation JAK2 Inhibitors in MPNs: Lilly’s $2.3B acquisition of Ajax Therapeutics signals major industry commitment to Type II (inactive-conformation) JAK2 inhibition via AJ1-11095 as a mechanistically distinct strategy for ruxolitinib/Type I-refractory myelofibrosis, complementing the AJ1-11095 Phase 1 trial already in the evidence base. (novelty: 4)
• 2026-03-24 — Karyopharm Phase 3 SENTRY Trial in Myelofibrosis Met First Co-Primary Endpoint: Phase 3 SENTRY trial of selinexor (XPO1 inhibitor) + ruxolitinib in MF met its co-primary spleen volume reduction endpoint with greater driver-allele VAF reduction (32% vs 24% achieving ≥20% reduction) than ruxolitinib alone, providing the first Phase 3 evidence that adding nuclear export inhibition potentiates JAK-STAT blockade, though symptom burden was not improved. (novelty: 4)
• 2026-04-27 — Clinical Impact of Next-Generation Sequencing-Detected Mutations on Thrombotic Events in Myeloproliferative Neoplasms.: JAK2/TET2 co-mutation in a 91-patient MPN NGS cohort was the strongest independent predictor of VTE, suggesting TET2 loss synergizes with JAK-STAT activation to amplify venous thrombotic risk. (novelty: 3)
• 2026-03-30 — JAK Inhibitor Before Donor Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis: Phase II trial evaluates pre-transplant ruxolitinib as bridging therapy in primary/secondary myelofibrosis to reduce splenomegaly and inflammation and improve fitness before allo-HCT, adding to the JAKi peri-transplant evidence base alongside HOVON-134 (pacritinib), momelotinib, and gecacitinib studies. (novelty: 3)
• 2026-04-08 — Fedratinib in Combination With Nivolumab: Phase II trial of fedratinib + nivolumab in JAKi-resistant/suboptimal-response MF tests whether layering PD-1 checkpoint blockade onto JAK-STAT inhibition can rescue patients failing prior JAK inhibitor therapy, extending the post-JAKi-failure combination portfolio into immune checkpoint territory. (novelty: 4)
• 2026-02-06 — Pacritinib For Bone Marrow Fibrosis In Patients With Myelofibrosis Who Have Thrombocytopenia: PACRIMYEL phase II trial tests pacritinib’s dual JAK2/IRAK1 inhibition specifically for bone marrow fibrosis reduction in moderately thrombocytopenic MF (platelets 50–120 ×10⁹/L), using MRI-based fibrosis quantification as a novel endpoint. (novelty: 4)
• 2026-03-04 — A Clinical Trial of Flonoltinib Maleate for Intermediate or High-Risk Myelofibrosis: Multicenter open-label positive-controlled trial of flonoltinib maleate (multi-kinase JAK2/FLT3/CDK6 inhibitor) versus active comparator in ~105 DIPSS intermediate/high-risk MF patients advances late-stage clinical evaluation of a non-ruxolitinib JAK inhibitor, complementing the FMF-02 head-to-head protocol. (novelty: 3)
• 2026-03-30 — A Study to Evaluate Safety , Efficacy and Pharmacokinetics of WJ01024 Tablets Combined With Ruxolitinib in Patients With Myelofibrosis: Phase Ib/II trial of WJ01024 tablets combined with ruxolitinib in intermediate-to-high-risk MF patients with poor response or intolerance to approved JAK inhibitors adds another investigational add-on partner to JAK-STAT blockade in the post-JAKi-failure setting. (novelty: 3)
• 2026-02-19 — Ruxolitinib Before, During and After Hematopoietic Cell Transplant in Older Patients With Myelofibrosis and Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes: Phase II trial extends ruxolitinib peri-transplant use (before, during, after allo-HCT) to older patients with myelofibrosis and MDS/MPN overlap syndromes, broadening the JAKi-as-GVHD-prophylaxis paradigm beyond MF alone and beyond gecacitinib/momelotinib analogues. (novelty: 3)
• 2026-04-27 — A Study of Roginolisib in Combination With Ruxolitinib in Patients With Myelofibrosis (MF) Who Are Unresponsive to JAK Inhibitors: Phase trial of roginolisib (PI3K inhibitor) + ruxolitinib in JAKi-unresponsive MF adds PI3K blockade to the growing portfolio of add-on partners (BCL-2/BCL-XL, BET, MDM2, XPO1, S100A9) layered onto JAK-STAT inhibition, here specifically targeting the post-JAKi-failure setting. (novelty: 3)
• 2026-03-23 — Study of Oral Navitoclax Tablet In Combination With Oral Ruxolitinib Tablet When Compared With Oral Ruxolitinib Tablet To Assess Change In Spleen Volume In Adult Participants With Myelofibrosis: Phase 3 navitoclax + ruxolitinib versus ruxolitinib trial advances the BCL-2/BCL-XL + JAK-STAT combination strategy from earlier REFINE phase 2 data into registrational evaluation in adult myelofibrosis. (novelty: 3)
• 2026-02-27 — Efficacy and Safety of Gecacitinib Hydrochloride in Prophylaxis Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Myelofibrosis: Gecacitinib hydrochloride (novel dual JAK/ACVR1 inhibitor) is being evaluated with ATG for aGVHD prophylaxis in myelofibrosis patients undergoing allo-HSCT, extending peri-transplant JAK-STAT blockade into the GVHD-prevention setting. (novelty: 4)
• 2026-04-24 — A Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of TQ05105 Tablets in Subjects With Intermediate/High-risk Myelofibrosis: Phase II trial of TQ05105 tablets in intermediate/high-risk MF refractory, relapsed, or intolerant to prior JAK inhibitor therapy adds another investigational JAK inhibitor to the post-JAKi-failure clinical portfolio. (novelty: 3)
• 2026-03-31 — Momelotinib During and After HCT in Myelofibrosis: Phase I trial of momelotinib administered during and after allogeneic HCT in myelofibrosis tests whether peri-transplant JAK-STAT blockade can be safely sustained through conditioning and engraftment, extending JAKi use beyond the bridging-only paradigm. (novelty: 4)
• 2026-03-24 — A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms: Combination of the mutCALR-targeting agent INCA033989 with ruxolitinib is being tested clinically, probing whether upstream mutCALR blockade plus JAK1/2 inhibition yields additive suppression of JAK-STAT-driven myeloproliferation. (novelty: 4)
• 2026-04-17 — A Study to Evaluate INCA033989 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasms: Phase 1 trial of INCA033989 (novel first-in-class agent) as monotherapy or in combination with ruxolitinib in MPN adds another investigational add-on partner to JAK-STAT blockade, joining the growing portfolio of ruxolitinib combination strategies. (novelty: 4)
• 2026-03-31 — Ruxolitinib Phosphate and Azacytidine in Treating Patients With Myelofibrosis or Myelodysplastic Syndrome/Myeloproliferative Neoplasm: Phase II trial of ruxolitinib + azacytidine in MF and MDS/MPN extends the HMA+JAKi combination paradigm (previously tested with decitabine in AP/BP MPN) to chronic MF and the MDS/MPN overlap setting. (novelty: 3)
• 2026-02-25 — A Phase 3 Study of Pacritinib in Patients With Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis: Phase 3 PACIFICA-style trial randomizes ~399 MF patients with severe thrombocytopenia (platelets <50,000/μL) 2:1 to pacritinib 200 mg BID versus physician’s choice, providing late-stage evidence that JAK-STAT blockade is achievable in the platelet-restricted MF subgroup where ruxolitinib/fedratinib are contraindicated. (novelty: 3)
• 2026-03-03 — A Clinical Study of Gecacitinib Combined With Pegylated Interferon in Patients With PV: Clinical trial of gecacitinib (novel JAK inhibitor) combined with pegylated interferon in PV evaluates a first-in-combination approach pairing JAK-STAT blockade with IFN-α-mediated clonal suppression over 24 weeks of hematological remission assessment. (novelty: 4)
• 2026-04-20 — Study of Momelotinib in Combination With Luspatercept in Participants With Transfusion Dependent Myelofibrosis: Phase 2 trial of momelotinib + luspatercept in transfusion-dependent MF tests a novel dual-mechanism strategy combining JAK-STAT blockade with ACVR2B ligand trap activity, extending JAKi combination paradigms beyond apoptotic/transcriptional partners to anemia-targeted erythroid maturation agents. (novelty: 4)
• 2026-03-16 — Decitabine With Ruxolitinib, Fedratinib or Pacritinib for the Treatment of Accelerated/Blast Phase Myeloproliferative Neoplasms: Phase II trial evaluates decitabine combined with ruxolitinib, fedratinib, or pacritinib as pre-transplant bridging therapy in accelerated/blast phase MPN, extending HMA+JAKi combination strategies across multiple JAK inhibitors in the AP/BP setting. (novelty: 3)
• 2026-03-06 — Identification of Factors Associated With Treatment Response in Patients With Polycythemia Vera, Essential Thrombocythemia, and Pre-myelofibrosis.: Prospective study integrates baseline NGS mutational profiling with cytokine profiling to predict 12-month hematological response to hydroxyurea or pegylated interferon in PV, ET, and pre-MF, supporting biomarker-guided selection among first-line cytoreductive (including JAK-STAT-modulating IFN) therapies. (novelty: 3)
• 2026-04-23 — Evaluation of HU-resistance in Adult Patients With Polycythemia Vera Who Meet PV-AIM Predictors: PV-AIM prospective validation study links baseline CBC-derived predictors (HGB <15.5 g/dL, RDW ≥17%) to hydroxyurea failure in PV, providing a clinical decision tool for escalating from HU to JAK-STAT–directed (ruxolitinib) or interferon-based therapy earlier. (novelty: 3)
• 2026-03-18 — Selinexor and Pacritinib in JAK Inhibitor-naïve MF Patients With Cytopenias: Phase II trial of pacritinib (JAK2/IRAK1 inhibitor) + selinexor in JAKi-naïve MF patients with anemia and thrombocytopenia extends XPO1+JAK combination strategies (previously tested with ruxolitinib) to the cytopenic MF subgroup where pacritinib’s platelet-sparing profile is preferred. (novelty: 4)
• 2026-04-24 — Testing the Effect of Taking Ruxolitinib and CPX-351 in Combination for the Treatment of Advanced Phase Myeloproliferative Neoplasms: Phase I/II trial of ruxolitinib + CPX-351 extends JAK-STAT blockade combination strategies into the accelerated/blast phase MPN setting, pairing JAK inhibition with liposomal anthracycline-cytarabine induction rather than the chronic-phase add-ons (navitoclax, navtemadlin, BET, selinexor) studied in JAKi-naïve MF. (novelty: 4)
• 2026-04-16 — A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF): Phase 3 trial of pelabresib (DAK539) + ruxolitinib in JAKi-naïve MF advances the BET+JAK combination paradigm to late-stage registrational evaluation, joining navitoclax, navtemadlin, selinexor, and tasquinimod as add-on strategies layered on JAK-STAT blockade. (novelty: 3)
• 2026-03-04 — Phase IIa Study on Flonoltinib Maleate Tablets in the Treatment of Patients With Polycythemia Vera: Phase IIa dose-exploration trial of flonoltinib maleate in hydroxyurea/interferon-resistant or intolerant PV patients extends evaluation of this multi-kinase JAK2/FLT3/CDK6 inhibitor (previously studied in MF via FMF-02) to the PV setting. (novelty: 4)
• 2026-04-01 — Safety and Tolerability Study of INCB057643 in Participants With Myelofibrosis and Other Advanced Myeloid Neoplasms: INCB057643 phase 1/2 trial joins navitoclax, navtemadlin, selinexor, and tasquinimod as another add-on combination strategy layering BET bromodomain inhibition onto ruxolitinib-mediated JAK-STAT blockade in MF. (novelty: 3)
• 2026-03-27 — A Phase 1 Study of AJ1-11095 in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) Who Have Been Failed by a Type I JAK2 Inhibitor (JAK2i): AJ1-11095 phase 1 trial tests whether type II (inactive-conformation) JAK2 inhibition can suppress JAK-STAT signaling in patients refractory to type I JAK2 inhibitors, addressing the persistence phenomenon where JAK-STAT output is reactivated despite type I JAKi therapy. (novelty: 4)
• 2026-02-27 — Open Label Phase 1/2 Study of Tasquinimod in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), or Post-Essential Thrombocytosis Myelofibrosis (Post-ET MF): Phase 1/2 trial of tasquinimod ± ruxolitinib introduces S100A9/innate-immune-axis inhibition as a mechanistically orthogonal partner to JAK-STAT blockade in MF, paralleling navitoclax, navtemadlin, selinexor, and BET-inhibitor add-on strategies. (novelty: 4)
• 2026-04-14 — Study of ZE74-0282 for Patients With JAK2 V617F Positive Blood Cancers: Early-phase trial of the novel agent ZE74-0282 targeting JAK2 V617F-positive blood cancers adds to the clinical-stage portfolio of JAK-STAT-directed therapeutics under evaluation. (novelty: 4)

Open questions

Related mechanisms

• calr-mutations
• mpl-mutations
• inflammatory-cytokine-signaling