MPL mutations

Current understanding

Activating mutations in the thrombopoietin receptor (MPL), most commonly W515L/K, drive JAK2 activation in a subset of ET and PMF.

Evidence log

• 2026-09-24 — Selective dependency of CALR-mutant myeloproliferative neoplasms on TYK2 signaling.: Preclinical evidence extends the TYK2-selective dependency to MPLW515K, showing that MPL-mutant signaling (like mutant CALR–MPL) requires TYK2 and is suppressed by deucravacitinib, offering a first mechanism-matched targeted strategy for MPL-driven MPN which has lagged CALR-directed efforts. (novelty: 5)
• 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 Phase 2b North American ET trial documented molecular responses to ropeginterferon alfa-2b in MPL-mutant patients, providing rare prospective clinical evidence that IFN-α can engage MPL-driven clones — a subgroup where IFN-α mechanism and response data have been especially limited. (novelty: 3)
• 2026-09-03 — Targeting Thrombopoietin/MPL Signaling to Mitigate JAK2V617F-Driven Cardiac Microvascular Disease.: Preclinical work extends MPL signaling relevance beyond hematopoietic activation to endocardial endothelium, where JAK2V617F-mutant blood cells upregulate endocardial TPO/MPL under cardiometabolic stress and anti-MPL neutralization rescues cardiac microvascular disease. (novelty: 4)
• 2026-08-20 — Mutational landscape of classical myeloproliferative neoplasms in the Western Cape Province, South Africa.: No MPL mutations were detected in the Western Cape South African classical MPN cohort, hinting at population-level rarity of MPL-driven disease in this setting (though small sample size may limit inference). (novelty: 3)
• 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.: Multidisciplinary characterization of rare MPL Y591 and R592 variants proposes they are not primary oncogenic drivers but potential disease modifiers, with Y591 substitutions predicted to disrupt a phosphorylation-dependent docking site and the YXXφ motif to yield TPO receptor hypersensitivity — extending the mutational mechanism catalogue beyond canonical W515 activation to sub-threshold receptor-modulating variants. (novelty: 4)
• 2026-06-23 — Galectin-1 Fuels Monocyte Hyperinflammation and Represents a Novel Therapeutic Target in Myeloproliferative Neoplasms.: In an MPLW515L murine model, genetic ablation of galectin-1 ameliorated splenomegaly, leukocytosis, and thrombosis, indicating that MPL-driven disease features are partly mediated through downstream monocyte LGALS1–TLR4–NF-κB inflammatory signaling. (novelty: 5)
• 2026 (rece — Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications: Review describes mutant CALR engaging MPL in a tetrameric complex that drives ligand-independent MPL activation, refining the structural model of how non-W515 (CALR-mediated) MPL activation occurs and surfaces the mutant CALR C-terminus extracellularly. (novelty: 3)
• 2026-06-18 — Resolving diagnostic uncertainty in rare MPL and CALR variants: A practical framework for the haematology clinic.: Proposed structural framework maps non-canonical MPL variants onto the transmembrane activation face, providing a mechanistic rationale (helical orientation of activating residues) to triage rare MPL VUS toward likely pathogenic vs. benign in routine MPN diagnostics. (novelty: 4)
• 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: AJ1-11095 initial clinical data report activity in MPL-mutant previously treated MF patients, providing early evidence that type II (inactive-conformation) JAK2 inhibition engages MPL-driven JAK2 activation in patients refractory to type I JAKi. (novelty: 4)
• 2026-06-05 — Eltrombopag as a Novel Therapeutic Approach for Low-risk MDS and CMML With TET2 Mutations: cross-connection with tet2-mutations: Eltrombopag links TET2-mutant clonal biology to MPL/TPO-receptor signaling, proposing that TPO-R agonism can selectively disadvantage TET2-mutant clones — a previously unconnected axis between an epigenetic driver and the thrombopoietin receptor pathway. (novelty: 4)
• 2026-06-01 — Cytokine receptor and JAK/STAT pathway mutations in acute myeloid leukemia: Prevalence and clinical impact.: MPL mutations contribute to the ~10% cytokine-receptor/JAK-STAT mutation prevalence in AML; like JAK2 and CALR, MPL in de novo AML yields intermediate outcomes attributable to co-mutational context rather than MPL signaling alone. (novelty: 3)
• 2026-06-02 — Genomic insights transform diagnosis, prognosis, and therapy in BCR::ABL1-negative myeloproliferative neoplasms.: Review groups MPL with JAK2 and CALR as a core driver whose detection should inform mutation-aligned diagnosis, prognosis, and emerging targeted therapy in BCR::ABL1-negative MPN. (novelty: 3)
• May 12, 20 — CALR Mutation–Directed Agents and Targeted Therapies Represent Key Research Avenue in MPN Management: Expert commentary lists MPL among the three driver mutations (JAK2, CALR, MPL) being prioritized for mutation-directed precision therapy in MPN, though MPL-specific agents lag CALR-directed efforts. (novelty: 3)
• 2026-04-14 — Mechanism of Action of Interferon in the Treatment of Myeloproliferative Neoplasms: Review of IFN-α mechanism in MPN notes limited mechanistic and response data in MPL-mutant disease, leaving how IFN-α engages MPL-driven clones largely unresolved. (novelty: 3)
• 2026-03-24 — Karyopharm Phase 3 SENTRY Trial in Myelofibrosis Met First Co-Primary Endpoint: Phase 3 SENTRY trial included MPL-mutant MF among driver subgroups showing ≥20% VAF reduction with selinexor + ruxolitinib (32% vs 24%), providing late-stage clinical evidence that combined XPO1 + JAK inhibition reduces MPL-mutant clone burden. (novelty: 4)

Open questions

Related mechanisms

• jak-stat-signaling
• calr-mutations