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

Temporal dynamics of the peripheral blood transcriptome are crucial for understanding leukemia evolution and response to therapy because they can reveal how gene expression programs drive abnormal cell states, disease heterogeneity, and treatment resistance. Using a mathematical model of state-transitions, we studied the temporal dynamics of peripheral blood messenger RNA (mRNA) and microRNA (miRNA) transcriptomes in a mouse model of acute myeloid leukemia (AML). In our model, mRNA and miRNA transcriptomes are represented as a particle undergoing Brownian motion in a two-dimensional multiomic potential landscape. Following chemotherapy, we observed an asymmetric shift in the landscape, leading to a temporal desynchronization between mRNA and miRNA transcriptomic responses. Specifically, mRNA trajectories responded almost immediately post-treatment, whereas miRNA responses were delayed by approximately two weeks. Clustering analysis identified that the temporal delay is driven by a prominent cluster of miRNAs from the imprinted Dlk1-Dio3 region on chromosomes 12qF1 in mice and 14q32 in humans. Although previously implicated in acute promyelocytic leukemia (APL), lymphomas, and metabolic dysregulation, this provides the first evidence linking the Dlk1-Dio3 locus to AML chemotherapy response and treatment-induced transcriptomic desynchronization. This framework offers an innovative dynamics-based strategy to identify biological drivers of therapeutic response and novel therapeutic targets across hematological malignancies. Key PointsO_LITreatment can induce desynchronization between messenger RNA and microRNA transcriptome dynamics in a murine model of AML C_LIO_LIMicroRNAs from the imprinted Dlk1-Dio3 locus are identified as key contributors to desynchronization and may serve as therapeutic targets C_LI