Multi-omic technologies and spatial transcriptomics help map leukemogenesis and resistance in hematologic malignanciesNew tools help map how blood cancers evolve and resist treatment

Leukemogenesis is a dynamic evolutionary process driven by interactions between cytogenetic lesions, epigenetic dysregulation, clonal selection, and the bone marrow microenvironment. Although recurrent chromosomal abnormalities and somatic mutations have transformed diagnosis and risk classification, conventional genomic approaches often incompletely resolve subclonal architecture, lineage plasticity, treatment resistance, and measurable residual disease (MRD). This narrative review examines how genetic and epigenetic alterations cooperate to initiate and sustain hematologic malignancies and how their temporal evolution shapes disease progression and therapeutic response. Particular emphasis is placed on recurrent cytogenetic abnormalities, DNA methylation, histone modification, chromatin remodeling, non-coding RNA regulation, clonal hematopoiesis, and interactions between leukemic cells and their microenvironment. Contemporary multi-omic technologies, including single-cell DNA and RNA sequencing, integrated single-cell multi-omics, spatial transcriptomics, and optical genome mapping, are critically evaluated for their capacity to resolve founder clones, cooperating lesions, subclonal trajectories, and lineage plasticity. The review further considers evolutionary mechanisms of resistance involving FLT3, TP53, BCL2-dependent survival, KMT2A–menin signaling, and BCR::ABL1 kinase-domain alterations, alongside emerging targeted therapies. Particular attention is given to MRD interpretation, including the distinction between persistent preleukemic clones and clinically relevant residual leukemia. Integrating longitudinal genomic, epigenetic, transcriptomic, and spatial information may enable more precise evolutionary monitoring and individualized treatment. This framework positions leukemogenesis as an adaptive ecosystem and supports precision hematology strategies designed to anticipate clonal escape, therapeutic resistance, disease progression, and relapse while improving molecularly informed clinical decision-making prospectively.