Clinical characteristics and whole exome sequencing in JAK2V617F- and CALR-unmutated essential thrombocythemia

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts.
• JAK2 V617F and CALR mutations are the most common driver mutations in ET.
• A subset of ET patients remains negative for these mutations, necessitating further investigation into their genetic landscape and clinical characteristics.

Purpose of the Study:

• To characterize the clinical features and outcomes of essential thrombocythemia (ET) patients with JAK2 V617F- and CALR-unmutated status.
• To identify potential driver mutations in this ET subgroup using whole-exome sequencing (WES).

Main Methods:

• A cross-sectional study of 162 ET patients diagnosed between 2007 and 2024.
• Clinical data and outcomes were compared between patients with and without JAK2 V617F and CALR mutations.
• Whole-exome sequencing (WES) was performed on 15 patients with JAK2 V617F- and CALR-unmutated ET.

Main Results:

• 24% (39/162) of ET patients were negative for JAK2 V617F and CALR mutations.
• This subgroup was younger (mean age 53.7 vs. 61.1 years) and had a trend towards lower thrombotic event incidence (5.1% vs. 9.1%) compared to JAK2 V617F-mutated ET.
• WES identified uncommon MPL mutations (e.g., MPL L265F, MPL P70L, MPL R321Q), potential novel CALR mutations, and non-driver mutations including RUNX1 (57.1%).

Conclusions:

• JAK2 V617F- and CALR-unmutated ET patients tend to be diagnosed at a younger age with a lower incidence of thrombosis.
• Whole-exome sequencing (WES) is crucial for detecting uncommon and potential driver mutations in this specific ET subgroup.
• Further research is warranted to elucidate the full spectrum of genetic alterations and their clinical impact in JAK2 V617F- and CALR-unmutated ET.