Despite the advent of potent tyrosine kinase inhibitors (TKIs), resistance and disease persistence remain significant clinical challenges in chronic myeloid leukemia (CML). This perspective aims to synthesize concepts derived from recent advances in single-cell and multi-omics analyses, which have revealed profound heterogeneity among leukemic stem cells (LSCs). These findings augment traditional models that focus solely on clonal selection and resistance-conferring mutations. We discuss how LSCs, like normal hematopoietic stem cells (HSCs), exist in a spectrum of transcriptionally and epigenetically defined cell states, each governed by distinct gene regulatory networks (GRNs) that confer unique lineage biases and responses to therapy. Incorporating recent insights from single-cell analysis, our perspective highlights evidence for a conserved chronic phase (CP) LSC state characterized by lineage skewing, altered metabolic and environmental responsiveness, and epigenetic dysregulation, features that are likely to be underpinned by specific GRN configurations that collectively contribute to intrinsic TKI resistance. We explore how both intrinsic factors (such as germline polymorphisms and lineage bias) and extrinsic cues (including microenvironmental signals, immune interactions, and hypoxia) are likely to modulate GRN activity and LSC states, thereby affecting apoptotic thresholds, primary resistance, and the potential for treatment-free remission (TFR). Emerging data support the concept of GRNdefined LSC states at diagnosis that are predictive of TKI responses. Furthermore, multiple studies suggest that blast crisis (BC) converges on a common high-risk transcriptomic and GRN state that is agnostic to mutational diversity, and driven by polycomb and DNA methylation-dependent epigenetic reprogramming. Given that BCR::ABL1-independent mechanisms, regulated at the level of GRNs, may contribute to resistance and LSC persistence, these observations support placing greater emphasis in CML management on addressing GRN-defined cell-state vulnerabilities, with the goal of lowering the risk of blast crisis in high-risk patients and improving control of therapy-resistant CP LSCs.
Krishnan et al. (Thu,) studied this question.