Abstract
Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS.
Highlights
Myelodysplastic syndromes (MDS) arise from a small population of disease-initiating hematopoietic stem cells (HSCs) that persist and expand through conventional therapies and are major contributors to disease progression[1–4]
To identify predictive biomarkers of MDS evolution, we first sought to characterize the immunophenotypic profile of the hematopoietic stem and progenitor cell (HSPC) compartment in a cohort of 123 bone marrow (BM) samples isolated from untreated patients with MDS
Unsupervised hierarchical clustering based on the frequency of immunophenotypically defined HSPC populations[1,12] (Supplementary Table 1) followed by principal-component analysis (PCA) identified the frequencies of the lymphoid-primed multipotent progenitor (LMPP) and granulocytic–monocytic progenitor (GMP) populations as the main sources of variation across the samples (Supplementary Fig. 1a)
Summary
MDS arise from a small population of disease-initiating HSCs that persist and expand through conventional therapies and are major contributors to disease progression[1–4]. In the last few years, single-cell technologies coupled with mouse functional studies have greatly improved our understanding of the molecular mechanisms driving MDS pathogenesis. Aberrant MDS cells that reside in the immunophenotypically defined HSC compartment are the source of disease progression[11], but how these cells contribute to therapy failure and disease evolution remains largely unknown. This gap in understanding is delaying the development of predictive biomarkers of clinical relapse and the design of second-line therapies for MDS that could greatly benefit patients in whom HMA-based therapy has failed. We sought to dissect the biological mechanisms that drive HMA therapy failure at the stem-cell level to uncover vulnerabilities in the disease and halt its evolution
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