Multiomic State-Transitions Reveal Post-Treatment Transcriptome Desynchronization in Acute Myeloid Leukemia

Area of Science:

• * Molecular biology
• * Systems biology
• * Hematologic oncology

Background:

• * Peripheral blood transcriptome dynamics are vital for understanding leukemia progression and treatment outcomes.
• * Gene expression patterns influence abnormal cell states, disease heterogeneity, and resistance to therapy.
• * Studying temporal transcriptomic changes provides insights into leukemia's complex behavior.

Purpose of the Study:

• * To investigate the temporal dynamics of messenger RNA (mRNA) and microRNA (miRNA) transcriptomes in a mouse model of acute myeloid leukemia (AML) after chemotherapy.
• * To model transcriptomic changes using a mathematical framework representing Brownian motion in a multiomic potential landscape.
• * To identify the molecular drivers behind chemotherapy-induced transcriptomic desynchronization.

Main Methods:

• * Utilized a mathematical model of state-transitions to analyze peripheral blood mRNA and miRNA transcriptomes.
• * Employed Brownian motion simulation within a two-dimensional multiomic potential landscape.
• * Performed clustering analysis to identify specific miRNA clusters responsible for temporal delays.

Main Results:

• * Observed an asymmetric shift in the multiomic potential landscape post-chemotherapy, causing desynchronization between mRNA and miRNA responses.
• * mRNA transcriptomes showed immediate response, while miRNA transcriptomes exhibited a delay of approximately two weeks.
• * Identified a prominent cluster of miRNAs from the imprinted Dlk1-Dio3 locus as the primary driver of this temporal delay.

Conclusions:

• * The Dlk1-Dio3 locus plays a significant role in AML chemotherapy response and treatment-induced transcriptomic desynchronization.
• * This study provides the first evidence linking the Dlk1-Dio3 locus to AML chemotherapy dynamics.
• * The developed framework offers a novel, dynamics-based approach for identifying therapeutic targets in hematologic malignancies.