Evolution of transcriptomic profiles in relapsed inv(16) acute myeloid leukemia

Area of Science:

• Hematology
• Molecular Biology
• Genomics

Background:

• Acute myeloid leukemia (AML) with inv(16) generally has a favorable prognosis.
• However, disease relapse occurs in up to 40% of patients, necessitating further research into prognostic markers and therapeutic vulnerabilities.

Purpose of the Study:

• To investigate the genomic and transcriptomic profiles of inv(16) AML to identify prognostic markers.
• To explore therapeutic vulnerabilities, particularly focusing on oxidative phosphorylation (OXPHOS) pathways at relapse.

Main Methods:

• Genomic and transcriptomic profiling of 222 diagnostic AML samples, including 44 relapse/refractory cases.
• RNA sequencing of diagnostic and relapse samples to identify pathway alterations.
• In vitro studies using the ME-1 cell line to assess the efficacy of Metformin in combination with Venetoclax/Azacitidine.

Main Results:

• The mutational landscape at diagnosis did not significantly differ between relapsed and non-relapsed patients, except for increased mutational burden in the relapsed group.
• Oxidative phosphorylation (OXPHOS) was identified as a significantly downregulated pathway in relapsed inv(16) AML.
• Metformin demonstrated a synergistic effect with Venetoclax/Azacitidine in vitro, enhancing chemosensitivity in the ME-1 cell line.

Conclusions:

• Downregulated OXPHOS expression at relapse in inv(16) AML presents a potential therapeutic target.
• Metformin shows promise as an adjunct therapy to enhance the efficacy of existing treatments like Venetoclax/Azacitidine in relapsed AML.