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Updated: Oct 8, 2026

Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
Published on: March 10, 2023
Outcome heterogeneity in CALR-mutated myeloproliferative neoplasms
Resham Mawalkar1, Hua-Ling Tsai2, Sergiu Pasca3
1Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract:
Calreticulin gene (CALR) mutations are seen in 25%-30% of myeloproliferative neoplasms (MPNs). We report outcomes and high-risk genomic signatures in 149 patients with CALR-mutated MPN. CALR-mutated essential thrombocythaemia (n = 106) progressed to myelofibrosis (n = 40) at a median of 20.4 years, and 20-year overall survival (OS) was 81%. In 83 patients with myelofibrosis, the median leukaemia-free survival (LFS) was 12.9 years, and OS was 13.9 years. Median survival after leukaemia transformation was 6.8 months. High molecular risk (HMR) mutations included ASXL1, EZH2, SRSF2, U2AF1 (Q157), IDH1/2, TP53, SETBP1, KRAS, NRAS and RUNX1 (later five not included in Mutation-Enhanced International Prognostic Score System [MIPSS70]-plus v2.0); and were associated with a significantly higher leukaemic transformation, inferior LFS and OS (hazard ratio [HR]: 3.82, 95% confidence interval [CI]: 1.30-11.18); with worst outcomes in patients with ≥2 HMR. Independent of MIPSS70-plus v2.0, TP53, KRAS and RUNX1 mutations adversely impacted LFS and OS (HR: 2.87, 95% CI: 1.20-6.88; HR: 3.80, 95% CI: 1.37-10.54; HR: 5.61, 95% CI: 1.53-20.52 respectively). Patients without HMR had a negligible rate of progression. Overall, outcomes are determined not by CALR 'driver' mutation, but by the somatic mutations that can emerge during disease evolution. Hence, serial molecular profiling is important for risk stratification. HMR, including TP53, KRAS and RUNX1, confer inferior survival and support early transplantation consideration.
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