Clonal hematopoiesis

Current understanding

MPN arises from clonal expansion of a single mutant hematopoietic stem cell. Allele burden, clonal architecture, and stem-cell competition shape disease trajectory.

Evidence log

• 2026-09-15 — Type 1 interferon perturbates clonal competition by reshaping human blood development.: Preclinical single-cell work reframes IFNα-driven clonal competition as a differentiation-bias phenomenon: mutant HSCs (CALR/JAK2) outcompete wild-type by resisting the inflammatory-myeloid differentiation program that IFNα imposes, refining the model of clonal fitness in a cytokine-perturbed niche. (novelty: 4)
• 2026-09-01 — Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesis.: Serial WGS integrated with clonal phylogenies and blood counts shows MPN clonal trajectories (including which patients will progress) are detectable years ahead of clinical change, and that a subset of triple-negative ET cases have no reconstructable neoplastic clone — suggesting some ‘MPN’ phenotypes are non-clonal in origin. (novelty: 4)
• 2026-06-16 — Allogeneic Transplantation in the Rare Disease Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Neutrophilia: Age and Disease Burden Determine Outcome.: In MDS/MPN with neutrophilia treated with allo-HCT (n=85), disease-burden features (marrow blasts, low hemoglobin) alongside TET2 and EZH2 co-mutations predicted worse post-transplant survival, reinforcing that clonal-context factors — not driver status alone — shape trajectory even after allogeneic replacement of hematopoiesis. (novelty: 3)
• 2026-08-12 — Additional myelodysplasia-related gene mutations alter clinical presentation and worsen prognosis in patients with/co-mutated myeloid neoplasms.: TET2-co-mutated myeloid neoplasms with additional MRG mutations (most often ASXL1) display distinct clinical phenotypes (less monocytosis, more anemia), halved survival, and higher AML transformation — further evidence that co-mutational clonal context, not driver identity alone, dictates disease trajectory. (novelty: 3)
• 2026-07-23 — DNMT3A and TET2 Mutations are Associated With Both Venous Thrombosis and Major Bleeding in Patients With Polycythemia Vera and Essential Thrombocythemia.: In PV and ET, non-driver DNMT3A and TET2 mutations — the two most common CHIP genes — were associated with both venous thrombosis and major bleeding, reinforcing that CHIP-type co-mutations shape clinical trajectory (here, hemostatic risk) beyond driver-allele status in chronic-phase MPN. (novelty: 3)
• 2026-07-31 — Unmasking Additional Mutations: A Single Institution Study in Myeloproliferative Neoplasms.: Single-institution 75-gene NGS at initial MPN evaluation uncovered additional pathogenic mutations in ~20% of patients — high-molecular-risk co-mutations in driver-positive cases and clonal/alternative-myeloid lesions in driver-negative cases — reinforcing that comprehensive baseline mutational profiling refines the clonal-architecture picture beyond driver-allele testing. (novelty: 3)
• 2026-07-13 — Mutational profile and cardiovascular risk factors impact prognosis in triple-negative essential thrombocythemia.: Triple-negative ET (lacking JAK2/CALR/MPL drivers) still carries prognostically meaningful clonal architecture — pathogenic ASXL1/CBL/EZH2/ZRSR2 mutations predict leukemic progression and shortened survival, showing that non-driver clonal context governs trajectory even without a classical MPN driver. (novelty: 3)
• 2026-08-03 — Non-invasive multiparametric characterization of essential thrombocythemia, premyelofibrosis, and overt myelofibrosis.: Multiparametric non-invasive profiling across ET, preMF, and overt PMF supports a pathophysiological continuum in which inflammatory and matrix-remodeling programs escalate along disease trajectory, complementing clonal-architecture models of MPN progression. (novelty: 3)
• 2026-08-01 — Inflammatory Network Architecture Across Bone Marrow Failure: An Immune-Genetic Continuum.: Cross-BMF review proposes that germline versus somatic genetic context biases the same inflammatory milieu toward HSC attrition (inherited BMF) versus clonal expansion (MPN/CH), framing clonal hematopoiesis as one outcome of a shared inflammation-genetics interaction. (novelty: 3)
• 2026-09-03 — Targeting Thrombopoietin/MPL Signaling to Mitigate JAK2V617F-Driven Cardiac Microvascular Disease.: Preclinical model shows JAK2V617F-mutant blood cells cause cardiac microvascular disease via endocardial TPO/MPL upregulation under cardiometabolic stress, expanding the end-organ consequences of the JAK2V617F clone beyond thrombosis and hematopoietic dysfunction. (novelty: 4)
• 2026-04-27 — JAK Inhibitor-Induced Improvement of IgA Nephropathy in a Patient With Polycythemia Vera: A Case Report.: Case report invokes aberrant hematopoietic IgA production from the MPN clone as a candidate contributor to concurrent IgA nephropathy, implicating clonal B-lineage/plasma cell output — not just myeloid expansion — as a route to end-organ immune-complex disease. (novelty: 4)
• 2026-06-15 — Replacing Bone Marrow Diagnostics With Peripheral Blood Analysis in MPN Patients: Proposes that single-cell RNA-seq profiling of circulating hematopoietic stem and progenitor cells in peripheral blood can recapitulate bone marrow clonal/transcriptional signatures sufficiently to diagnose and subtype MPN, implying that the clonal HSPC compartment is detectably represented in the peripheral circulation. (novelty: 4)
• 2026-06-10 — Ropeginterferon for High Risk JAK2 Clonal Hematopoiesis: Early-phase clinical trial of ropeginterferon alfa-2b in high-risk JAK2 clonal hematopoiesis (without overt MPN) tests disease interception at the pre-MPN clonal stage, extending IFN-α’s hypothesized mutant-HSC-depleting mechanism upstream of overt myeloproliferative disease. (novelty: 4)
• 2026-06-05 — Eltrombopag as a Novel Therapeutic Approach for Low-risk MDS and CMML With TET2 Mutations: Eltrombopag is being trialed as a TET2-mutation-selective cytoreductive agent in low-risk MDS/CMML, suggesting that TPO-R signaling modulation may differentially affect mutant versus wild-type clones in the CHIP-to-MDS continuum. (novelty: 4)
• 2026-06-01 — Cytokine receptor and JAK/STAT pathway mutations in acute myeloid leukemia: Prevalence and clinical impact.: Observational AML cohort (n=971) shows blast-phase MPN has a far worse response rate (13%) than de novo AML harboring the same JAK2/CALR/MPL drivers, implicating accumulated clonal-evolution context (co-mutations, prior MPN clone history) — rather than driver mutation identity — as the dominant determinant of leukemic aggressiveness. (novelty: 3)
• 2026-06-02 — Genomic insights transform diagnosis, prognosis, and therapy in BCR::ABL1-negative myeloproliferative neoplasms.: Review argues that integrating mutational profiling with clonal architecture analysis refines MPN diagnosis and prognosis and enables molecular monitoring beyond driver-allele tracking alone. (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 study proposes that JAK2V617F-mutated endothelial cells with embryonic-like hemogenic potential may be the true cell of origin for the PMF clone, challenging the canonical HSC-centric model of clonal hematopoiesis in MPN. (novelty: 5)
• 2026-05-10 — Scalable genotyping in fixed transcriptomes resolves clonal heterogeneity via single-cell sequencing: Scalable single-cell genotyping with whole-transcriptome capture (GIFT) links mutant JAK2 allele dose within individual HSCs to divergent transcriptional priming, supporting the model that intra-clonal heterogeneity in allele dosage — not just mutation presence — drives disease-trajectory branching across MPN phenotypes. (novelty: 5)
• 2026-05-15 — Identification of MPN-specific Antigens and Anti-MPN TCRs in Myeloproliferative Neoplasm: Observational study to identify MPN-specific antigens and cognate TCRs implies the MPN clone harbors immunogenic neoantigens (likely from driver mutations like CALR/JAK2) that could be exploited to selectively target the clonal compartment. (novelty: 4)
• 2026-04-14 — Mechanism of Action of Interferon in the Treatment of Myeloproliferative Neoplasms: Mechanistic review frames pegylated IFN-α as a therapy that preferentially targets malignant HSCs to reduce clonal burden, while flagging that the molecular determinants of deep molecular response and the differential clearance of JAK2- versus CALR-mutant clones remain poorly understood. (novelty: 3)
• 2026-03-09 — Clonal Architecture of ASXL1-mutated Myelofibrosis: Prospective profiling of ASXL1-mutated PMF and SMF links specific clonal architecture patterns to outcome, supporting clonal architecture (not just mutation presence) as a prognostic axis in myelofibrosis. (novelty: 3)
• 2026-03-27 — Curcumin to Improve Inflammation and Symptoms in Patients With Clonal Cytopenia of Undetermined Significance, Low Risk Myelodysplastic Syndrome, and Myeloproliferative Neoplasms: Phase II curcumin trial spans the CCUS-to-MPN clonal continuum, implicitly testing whether dampening inflammation in precursor and overt clonal states modifies symptom trajectory across the clonal hematopoiesis spectrum. (novelty: 3)
• 2026-03-06 — Identification of Factors Associated With Treatment Response in Patients With Polycythemia Vera, Essential Thrombocythemia, and Pre-myelofibrosis.: Protocol study proposes baseline NGS mutational profile as a candidate predictor of 12-month hematological response to hydroxyurea or pegylated interferon in PV, ET, and pre-MF, extending the prognostic role of clonal architecture into therapy selection. (novelty: 3)
• 2026-04-01 — A novel approach to defining progression in MDS and precursor myeloid conditions in the MDS Natural History Study.: In the prospective MDS Natural History Study, progression from precursor states (ICUS/CCUS) to MDS was predicted by higher mutation burden, TP53 mutation, poor cytogenetics, and female sex, linking clonal hematopoiesis features to quantifiable progression risk (17% in ICUS/IDUS up to 73% in higher-risk MDS). (novelty: 3)
• 2026-04-27 — Mutations in CHIP-associated genes at myeloid neoplasm diagnosis and risk of cardiovascular/cerebrovascular events.: CHIP-associated mutations detected at myeloid neoplasm diagnosis were not independently associated with incident cardiovascular/cerebrovascular events after multivariable adjustment, though patients ≥70 with mutations showed the highest observed risk — suggesting CHIP’s cardiovascular signal may be attenuated or confounded once overt myeloid neoplasia is established. (novelty: 3)
• 2026-04-27 — Clinical Impact of Next-Generation Sequencing-Detected Mutations on Thrombotic Events in Myeloproliferative Neoplasms.: 78-gene NGS profiling of 91 MPN patients shows specific co-mutation patterns (JAK2/TET2 for VTE; ASXL1/splicing factors for arterial events and fibrosis) shape clinical trajectory beyond driver mutation status alone. (novelty: 3)
• 2026-03-06 — Interest of CALR Allele Burden in Diagnosis and Follow-up of Patients With CALR Mutated Myeloproliferative Syndromes (CALRSUIVI): CALRSUIVI prospectively tracks CALR clone size over time, supporting allele burden as a quantitative readout of clonal dynamics in MPN follow-up. (novelty: 3)

Open questions

Related mechanisms

• tet2-mutations
• asxl1-mutations
• jak-stat-signaling