Single-cell and spatial multi-omics to decode clonal evolution and therapeutic resistance in hematologic malignancies

Hematologic malignancies — including acute myeloid leukemia (AML), T-cell and B-cell lymphomas, myeloproliferative neoplasms, and myelodysplastic syndromes — are characterized by profound intratumoral heterogeneity arising from the dynamic clonal evolution of malignant precursors within the bone marrow niche and secondary lymphoid organs. Conventional bulk genomic and transcriptomic approaches have advanced our understanding of disease biology, but they mask the cellular complexity underlying tumor initiation, progression, and relapse. Single-cell technologies — including single-cell RNA sequencing (scRNA-seq), single-cell ATAC-seq, and spatial transcriptomics — have emerged as transformative tools that resolve this heterogeneity at unprecedented resolution, enabling the mapping of clonal hierarchies, the identification of rare cell states, and the dissection of the tumor microenvironment at single-cell and spatial levels. When integrated with multi-omics platforms — combining genomics, epigenomics, proteomics, and metabolomics — these approaches are reshaping our understanding of how leukemic and lymphoma stem cells evolve, adapt, and evade therapeutic pressure. Despite rapid methodological advances, their systematic application to clinical cohorts of hematologic malignancies, and their integration with translational and preclinical modeling frameworks, remains an evolving and incompletely mapped frontier.The central challenge in the clinical management of hematologic malignancies is the incomplete eradication of malignant clones — including leukemic and lymphoma stem cells — that persist through treatment, drive relapse, and underpin therapeutic resistance. Understanding the mechanisms by which these clones evolve, maintain stemness, exploit the bone marrow niche, and acquire resistance to targeted agents, venetoclax, immunotherapy, and cellular therapies requires tools that go beyond bulk sequencing. Recent advances in single-cell and spatial multi-omics have revealed that clonal evolution is not a linear process but rather a dynamic, spatially constrained, and microenvironment-dependent phenomenon. Key questions remain: How do epigenetic and transcriptional reprogramming cooperate to sustain leukemic stem cell identity and drug tolerance? How does the bone marrow niche shape clonal fitness and resistance? How can spatial transcriptomics resolve the geographic distribution of resistant subclones within tissue? And how can patient-derived organoids and preclinical avatars accelerate the translation of single-cell discoveries into actionable therapeutic strategies?This Research Topic aims to consolidate cutting-edge single-cell and spatial multi-omics research applied to hematologic malignancies, bridging molecular discovery with clinical relevance. It seeks to bring together studies that decode clonal architecture, map the tumor microenvironment, characterize resistance mechanisms, and define novel therapeutic vulnerabilities across the spectrum of blood cancers — from AML and T-cell malignancies to lymphomas, myeloproliferative neoplasms, and myelodysplastic syndromes.This Research Topic welcomes Original Research, Review, Mini Review and Perspective articles on themes including:- Single-cell transcriptomic and epigenomic profiling of leukemic and lymphoma stem cells and their niches- Spatial transcriptomics and proteomics to resolve the tumor microenvironment in hematologic malignancies- Clonal evolution and dynamics of drug resistance decoded by single-cell multi-omics- RAS family gene alterations and oncogenic signaling in AML: single-cell and translational perspectives- Bone marrow niche interactions and their role in sustaining leukemic and hematopoietic stem cell homeostasis- Epigenetic reprogramming and chromatin remodeling as drivers of therapeutic resistance- Patient-derived organoids and preclinical avatars for modeling clonal heterogeneity and drug response- T-cell receptor and B-cell receptor repertoire analysis by single-cell sequencing in lymphoid malignancies- Integration of single-cell omics with next-generation sequencing for clonality assessment and MRD monitoring- Computational frameworks, machine learning, and AI tools for multi-omics data integration in hematology- Histone deacetylase inhibitors and other epigenetic therapies: mechanisms of action and resistance at single-cell resolution- Single-cell approaches to characterize rare hematologic malignancies and atypical disease presentationsPlease note: manuscripts consisting solely of bioinformatics or computational analysis of sole public databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic. Topic editors: Pier Paolo Piccaluga, Giuseppe Visani, Fisnik Kurshumliu Source: https://www.frontiersin.org/research-topics/80398/single-cell-and-spatial-multi-omics-to-decode-clonal-evolution-and-therapeutic-resistance-in-hematologic-malignancies