Mutations and thrombosis in essential thrombocythemia

Guglielmelli, Paola; Gangat, Naseema; Coltro, Giacomo; Lasho, Terra L.; Loscocco, Giuseppe Gaetano; Finke, Christy; Morsia, Erika; Sordi, Benedetta; Szuber, Natasha; Hanson, Curtis A.; Pardanani, Animesh; Vannucchi, Alessandro M.; Tefferi, Ayalew

doi:10.1038/s41408-021-00470-y

Cited by 32 publications

(36 citation statements)

References 14 publications

(1 reference statement)

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“… 24 , 25 Mutations in the ASXL1 gene are relatively scarce in patients with polycythemia vera and essential thrombocythemia (7%-20%) but are found in 19% to 40% of patients with primary myelofibrosis. 26 , 27 A small minority of patients with MPNs harbor mutations in DNMT3A , with a frequency of approximately 9% in patients with polycythemia vera and essential thrombocythemia and in 3% to 15% of patients with primary myelofibrosis. 28 , 29 …”

Section: Influence Of Driver Mutations and Chip-associated Mutations ...mentioning

confidence: 99%

“… 20 Interestingly, in patients with essential thrombocythemia, ASXL1 mutations were associated with a decreased risk for thrombosis, while JAK2 V617F was associated with increased thrombosis. 27 Yet in patients with primary myelofibrosis and essential thrombocytosis, mutations in ASXL1 were associated with worse survival and increased risk for leukemic transformation. 33 , 34 The presence of CHIP-associated mutations in patients with MPN is likely associated with worse outcomes; however, their impact on cardiovascular events and outcomes requires further thorough investigation.…”

Section: Influence Of Driver Mutations and Chip-associated Mutations ...mentioning

confidence: 99%

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Cardiovascular Disease in Myeloproliferative Neoplasms

Leiva

Hobbs

Ravid

et al. 2022

JACC: CardioOncology

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Section: Influence Of Driver Mutations and Chip-associated Mutations ...mentioning

confidence: 99%

Section: Influence Of Driver Mutations and Chip-associated Mutations ...mentioning

confidence: 99%

Cardiovascular Disease in Myeloproliferative Neoplasms

Leiva

Hobbs

Ravid

et al. 2022

JACC: CardioOncology

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“… 7 More recently, collaborative studies between the Mayo Clinic, Rochester, USA and University of Florence, Italy, established an integrated clinical and genetic survival risk model for ET (MIPSS‐ET) identifying the presence of SF3B1 and SRSF2 mutations (occurring in ∼10% of patients), age > 60 years, male sex, and leukocytosis (≥ 11 × 10 9 /L) as independent risk factors for reduced overall survival 8 ; this collaborative effort also identified SF3B1 and U2AF1 mutations as risk factors for fibrotic progression and highlighted the protective role on arterial thrombosis of ASXL1 , RUNX1 and EZH2 mutations. 9 Myelofibrotic transformation was reported to be significantly higher among CALR ‐mutated ET patients than JAK2 V617F patients in one initial report. 10 Follow‐up studies were inconsistent, some showing no increased risk of transformation 11 , 12 but one large‐scale study again found a higher risk of transformation to MF.…”

Section: Introductionmentioning

confidence: 97%

“…Classically, survival prediction in ET was based on clinically‐derived risk variables, including age, thrombosis history and leukocyte count 7 . More recently, collaborative studies between the Mayo Clinic, Rochester, USA and University of Florence, Italy, established an integrated clinical and genetic survival risk model for ET (MIPSS‐ET) identifying the presence of SF3B1 and SRSF2 mutations (occurring in ∼10% of patients), age > 60 years, male sex, and leukocytosis (≥ 11 × 10 9 /L) as independent risk factors for reduced overall survival 8 ; this collaborative effort also identified SF3B1 and U2AF1 mutations as risk factors for fibrotic progression and highlighted the protective role on arterial thrombosis of ASXL1 , RUNX1 and EZH2 mutations 9 10 .…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients

et al. 2021

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The current retrospective study involving a total of 1607 patients was designed to identify clinical and molecular variables that were predictive of inferior myelofibrosis‐free survival (MFS) in WHO‐defined essential thrombocythemia (ET), utilizing three independent patient cohorts: University of Florence, Italy (n = 718); Mayo Clinic, USA (n = 479) and Policlinico Gemelli, Catholic University, Rome, Italy (n = 410). The Florence patient cohort was first examined to identify independent risk factors for MFS, which included age > 60 years (HR 2.5, 95% CI 1.3–4.9), male sex (2.1, 1.2–3.9), palpable splenomegaly (2.1, 1.2–3.9), CALR 1/1‐like or MPL mutation (3.4, 1.9–6.1) and JAK2V617F variant allele frequency > 35% (4.2, 1.6–10.8). Subsequently, an operational molecular risk category was developed and validated in the other two cohorts from Mayo Clinic and Rome: “high molecular risk” category included patients with JAK2V617F VAF >35%, CALR type 1/1‐like or MPL mutations; all other driver mutation profiles were assigned to “low molecular risk” category. The former, compared to the latter molecular risk category, displayed significantly higher risk of fibrotic transformation: Florence cohort with respective fibrotic transformation risk rates of 8% vs. 1.2% at 10 years and 33% vs. 8% at 20 years (p < 0.001; HR 6.1; 95% CI 3.2–11.7); Mayo Cohort, 16% vs. 7% at 10 years and 44% vs. 25% at 20 years (p < 0.001; HR 2.5; 95% CI 1.6–4.1); and Rome cohort 7.8% vs. 4.6% at 10 years and 31.2% vs. 7.1% at 20 years (p = 0.007, HR 2.7; 95% CI 1.3–5.8). The present study provides practically useful risk signals for fibrotic transformation in ET and facilitates identification of patients who require close monitoring and appropriate counseling.

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“…Conversely, MIPSS-ET included male sex; age >60 years; leukocyte count ≥11 × 10 9 /L; and the presence of mutations in SRSF2, SF3B1, U2AF1, or TP53. A recent sub-analysis of the ET cohort included in the MIPSS-ET demonstrated that ASXL1/RUNX1/EZH2 mutations were associated with a decreased risk of arterial thrombosis, suggesting a different underlying biology [96]. These interesting and promising results require further studies to determine their practical role in clinical management.…”

Section: Polycythemia Vera and Essential Thrombocythemiamentioning

confidence: 99%

Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms

Loscocco

Coltro

Guglielmelli

et al. 2021

Cells

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Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hematopoietic stem cell, characterized by an abnormal proliferation of largely mature cells driven by mutations in JAK2, CALR, and MPL. All these mutations lead to a constitutive activation of the JAK-STAT signaling, which represents a target for therapy. Beyond driver ones, most patients, especially with myelofibrosis, harbor mutations in an array of “myeloid neoplasm-associated” genes that encode for proteins involved in chromatin modification and DNA methylation, RNA splicing, transcription regulation, and oncogenes. These additional mutations often arise in the context of clonal hematopoiesis of indeterminate potential (CHIP). The extensive characterization of the pathologic genome associated with MPN highlighted selected driver and non-driver mutations for their clinical informativeness. First, driver mutations are enlisted in the WHO classification as major diagnostic criteria and may be used for monitoring of residual disease after transplantation and response to treatment. Second, mutation profile can be used, eventually in combination with cytogenetic, histopathologic, hematologic, and clinical variables, to risk stratify patients regarding thrombosis, overall survival, and rate of transformation to secondary leukemia. This review outlines the molecular landscape of MPN and critically interprets current information for their potential impact on patient management.

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Mutations and thrombosis in essential thrombocythemia

Cited by 32 publications

References 14 publications

Cardiovascular Disease in Myeloproliferative Neoplasms

Cardiovascular Disease in Myeloproliferative Neoplasms

Clinical and molecular predictors of fibrotic progression in essential thrombocythemia: A multicenter study involving 1607 patients

Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms

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