Altered NFE2 activity predisposes to leukemic transformation and myelosarcoma with AML-specific aberrations

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Acquired genetic aberrations are critical in acute myeloid leukemia (AML) prognosis and treatment.
• Novel aberrations are increasingly incorporated into clinical decision-making algorithms.
• Transcription factor NFE2 mutations were previously identified in myeloproliferative neoplasms.

Purpose of the Study:

• To report the presence and functional characterization of NFE2 mutations in AML and myelosarcoma patients.
• To investigate the role of NFE2 mutations in the progression of hematologic malignancies.
• To explore the acquisition of secondary genetic alterations in the context of NFE2 mutations.

Main Methods:

• Analysis of NFE2 mutations in patient samples (AML and myelosarcoma).
• Expression of mutant NFE2 in a mouse model to study disease development.
• Longitudinal monitoring of mice for disease transformation and acquisition of genetic aberrations.

Main Results:

• Expression of mutant NFE2 in mice induced a myeloproliferative phenotype.
• 34% of mice with mutant NFE2 transformed to leukemia or developed myelosarcomas.
• These secondary malignancies acquired AML-specific alterations, including trisomy 8, 5q deletion, and Trp53 mutations.

Conclusions:

• Mutations in NFE2 predispose to the development of myelosarcoma and/or AML.
• NFE2 mutations facilitate the acquisition of secondary genetic changes that drive leukemogenesis and sarcomagenesis.
• NFE2 mutations represent a potential therapeutic target in specific hematologic malignancies.