CALR mutations

Current understanding

Frameshift mutations in calreticulin (CALR) exon 9 — type 1 (52bp deletion) and type 2 (5bp insertion) — drive MPL receptor activation in CALR-mutant ET and PMF.

Evidence log

• 2026-10-07 — Outcome heterogeneity in CALR-mutated myeloproliferative neoplasms.: Observational cohort finds that outcomes in CALR-mutated MPN are driven primarily by acquired high-molecular-risk co-mutations (TP53, KRAS, RUNX1) rather than the CALR driver itself, with these co-mutations independently worsening LFS/OS and extending HMR definitions beyond MIPSS70-plus v2.0. (novelty: 3)
• 2026-09-30 — Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Mutant Calreticulin Targeted Antibodies in CALR-mutant Myeloproliferative Neoplasms: Phase 1/1b trial of DMR-001, a mutant-CALR-targeted antibody, launched evaluating safety, PK, immunogenicity, and preliminary efficacy as monotherapy in CALR-mutant ET/MF and in combination with ruxolitinib in CALR-mutant MF — adding a second first-in-class mutant-CALR antibody program alongside INCA033989 and JNJ-88549968. (novelty: 4)
• 2026-09-28 — Mutant CALR-peptide Based Vaccine in Patients With Mutated CALR Myeloproliferative Neoplasm: Early-phase trial launched evaluating a mutant CALR peptide vaccine for safety and tolerability in CALR-mutant MPN patients, extending the mutant-CALR neoepitope therapeutic strategy from antibodies (INCA033989) and T-cell engagers (INCA035784) to active immunization via neoantigen vaccination. (novelty: 4)
• 2026-09-24 — Selective dependency of CALR-mutant myeloproliferative neoplasms on TYK2 signaling.: Preclinical mechanistic study identifies TYK2 as a selective signaling dependency of CALR-mutant (del52, ins5) MPN, with deucravacitinib ± fedratinib suppressing CALR-mutant clones and ET/PMF colonies — nominating a genotype-matched pharmacologic vulnerability distinct from JAK2V617F disease. (novelty: 5)
• 2026-09-15 — Type 1 interferon perturbates clonal competition by reshaping human blood development.: Single-cell multiomic evidence suggests CALR-mutant HSCs share with JAK2-mutant HSCs a resistance to IFNα-induced inflammatory myeloid differentiation, offering a candidate mechanistic basis for CALR-mutant clone persistence under IFNα despite generally weaker molecular responses than JAK2V617F. (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 reports molecular responses to ropeginterferon alfa-2b in CALR-mutant ET patients alongside JAK2 and MPL subgroups, providing prospective North American ET evidence that IFN-α-mediated clonal suppression is engageable in CALR-driven disease despite historically weaker molecular responses than JAK2V617F. (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 combination data suggest selinexor + ruxolitinib activity in MF progenitors extends across driver genotypes, complementing SENTRY Phase 3 observations of VAF reduction in CALR-mutant patients. (novelty: 3)
• 2026-08-20 — Mutational landscape of classical myeloproliferative neoplasms in the Western Cape Province, South Africa.: South African Western Cape MPN cohort reported an unusually low CALR mutation frequency versus international benchmarks, raising the possibility of population/ancestry-specific differences in CALR-driven MPN prevalence. (novelty: 3)
• 2026 (rece — Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications: Review synthesizes structural evidence that the mutant CALR–MPL complex assembles as a tetramer with the mutant CALR C-terminus exposed on the cell surface, providing a mechanistic basis for both constitutive MPL activation and the accessibility of the neo-C-terminus to therapeutic antibodies (e.g., INCA033989). (novelty: 3)
• December 7 — Early Data Show Mutant CALR-Specific Monoclonal Antibody Well Tolerated in Myelofibrosis: ASH 2025 early clinical data show INCA033989 (mutant CALR-specific monoclonal antibody) is well tolerated as monotherapy and in combination with ruxolitinib in myelofibrosis patients, supporting safety of selective neoepitope targeting in the MF setting. (novelty: 4)
• May 1, 202 — Myelofibrosis (MF) in 2026: Matching Therapy to the Dominant Clinical Problem: Narrative review frames mutation-specific CALR-directed agents (INCA033989, bispecific antibodies) as central to matching MF therapy to the dominant clinical problem, consolidating CALR neoepitope targeting within the 2026 MF treatment paradigm. (novelty: 3)
• June 12-15 — Advancing Frontiers in Myeloproliferative Neoplasms - EHA 2025 Congress Review: EHA 2025 congress review highlights INCA035784, a novel T cell-redirecting (bispecific) antibody targeting mutant CALR, extending the mutant-CALR neoepitope therapeutic strategy beyond passive antibodies (e.g., INCA033989) into T cell engager modalities. (novelty: 3)
• 2026-06-18 — Resolving diagnostic uncertainty in rare MPL and CALR variants: A practical framework for the haematology clinic.: Practical interpretive framework uses predicted C-terminal charge profile of non-canonical CALR variants — extending the mutant-CALR positively-charged neo-C-terminus paradigm of type 1/2 frameshifts — to distinguish likely pathogenic rare variants from true VUS in clinical workup. (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 in previously treated MF include responses in CALR type 1 and type 2 mutant patients, indicating that type II JAK2 inhibition can suppress disease driven by mutant CALR-MPL-JAK2 signaling, not only JAK2V617F-driven clones. (novelty: 4)
• 2026-06-03 — A Phase 3 Study of INCA033989 Versus Best Available Therapy in Participants With Essential Thrombocythemia: Phase 3 trial launched evaluating INCA033989 (first-in-class mutant-selective CALR-targeting antibody) versus best available therapy in CALR-mutant ET patients previously treated with cytoreductive therapy, advancing mutant-CALR neoepitope targeting to late-stage clinical validation in ET. (novelty: 4)
• 2026-06-01 — Cytokine receptor and JAK/STAT pathway mutations in acute myeloid leukemia: Prevalence and clinical impact.: CALR mutations are rare in de novo AML; when present, outcomes are intermediate and appear shaped by co-occurring high-risk lesions rather than the CALR mutation itself, contrasting with the dismal prognosis of blast-phase MPN. (novelty: 3)
• 2026-06-02 — Genomic insights transform diagnosis, prognosis, and therapy in BCR::ABL1-negative myeloproliferative neoplasms.: Review reinforces CALR mutational profiling and CALR-directed agents as central to mutation-aligned MPN diagnosis and disease-modifying therapy, alongside JAK2 and MPL. (novelty: 3)
• May 21, 20 — CALR Mutation–Directed Agents and Targeted Therapies Represent Key Research Avenue in MPN Management: Review synthesis frames mutant-CALR–directed agents (e.g., INCA033989) alongside SENTRY (selinexor+ruxolitinib), MANIFEST-3 (pelabresib), and IMpactMF (imetelstat) as the defining combination and precision-targeted research avenues in MPN. (novelty: 3)
• November 1 — New Essential Thrombocythemia Treatment Appears to Address Underlying Disease: Early-phase trial in 49 ET patients reported INCA033989 (anti-mutant CALR antibody) achieved 66% complete platelet response and reduced mutCALR VAF in 89% of evaluable patients, extending prior MF evidence of disease-modifying activity to the ET setting and reinforcing mutant CALR neoepitope targeting as clinically tractable. (novelty: 4)
• May 22, 20 — All Eyes Are on Novel Combination Therapies and Molecular Targets in MPN at ASH 2025: ASH 2025 conference review reaffirms mutant CALR-targeted therapies as a defining MPN research direction alongside MANIFEST-2 96-week pelabresib+ruxolitinib data, situating CALR neoepitope targeting within the broader combination-therapy landscape. (novelty: 3)
• March 24, — ASH 2025: Myelofibrosis Roundup: ASH 2025 Phase 1 data for INCA033989 (first-in-class anti-mutant CALR antibody) reported 87% treatment retention with spleen volume reduction, anemia improvement, and symptom reduction in MF patients including JAKi-resistant/intolerant — first clinical evidence that direct immunologic targeting of the mutant CALR neoepitope produces disease-modifying activity. (novelty: 5)
• May 12, 20 — CALR Mutation–Directed Agents and Targeted Therapies Represent Key Research Avenue in MPN Management: Expert review highlights mutant-CALR–directed agents as a key emerging precision-medicine avenue in MPN, framing CALR-specific therapeutics alongside JAK2/MPL-targeted approaches as a defining research direction. (novelty: 3)
• 2026-05-15 — Identification of MPN-specific Antigens and Anti-MPN TCRs in Myeloproliferative Neoplasm: cross-connection with mpn-specific-antigens-tcr-immunotherapy: CALR frameshift mutations generate a shared neoantigenic C-terminal peptide, making CALR-mutant MPN a leading source of candidate antigens for anti-MPN TCR discovery. (novelty: 4)
• 2026-02-25 — Evaluation of the Pathobiology of CALR-mutated MPN Cells: Preclinical pathobiology study identifies distinct cellular features of CALR-mutated MPN cells (vs. JAK2-mutated) that may mechanistically underlie the lower thrombosis risk observed clinically in CALR-mutant patients. (novelty: 3)
• 2026-04-14 — A Study of JNJ-88549968 for the Treatment of Calreticulin (CALR)-Mutated Myeloproliferative Neoplasms: Phase 1/2 trial of JNJ-88549968, a novel agent specifically targeting CALR-mutated MPNs, launched as monotherapy and in combination with ruxolitinib or momelotinib in CALR-mutant ET/MF — represents the first dedicated mutant-CALR-directed therapeutic mechanism entering clinical evaluation. (novelty: 4)
• 2026-04-14 — Mechanism of Action of Interferon in the Treatment of Myeloproliferative Neoplasms: Review emphasizes that CALR-mutant MPN patients show heterogeneous and generally lower molecular responses to pegylated interferon-α than JAK2V617F patients, identifying CALR-mutant IFN response biology as a key open question in MPN mechanism research. (novelty: 3)
• 2026-03-06 — Interest of CALR Allele Burden in Diagnosis and Follow-up of Patients With CALR Mutated Myeloproliferative Syndromes (CALRSUIVI): 2026 — CALRSUIVI prospective observational study evaluated CALR allele burden as a molecular marker, supporting its utility for disease progression monitoring and follow-up in CALR-mutant MPN, analogous to JAK2 V617F allele burden tracking. (novelty: 3) (novelty: 3)
• 2026-03-24 — Karyopharm Phase 3 SENTRY Trial in Myelofibrosis Met First Co-Primary Endpoint: Phase 3 SENTRY trial reported VAF reductions extending to CALR-mutant patients in the selinexor + ruxolitinib arm, suggesting XPO1 inhibition can deepen molecular response in CALR-driven MF beyond JAK-STAT blockade alone. (novelty: 4)

Open questions

Related mechanisms

• jak-stat-signaling
• mpl-mutations