Faculty, Staff and Student Publications
Publication Date
3-1-2022
Journal
Nature Medicine
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.
Keywords
Bridged Bicyclo Compounds, Heterocyclic, Hematopoietic Stem Cells, Humans, Myelodysplastic Syndromes, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, Stem cells, Cancer stem cells
DOI
10.1038/s41591-022-01696-4
PMID
35241842
PMCID
PMC8938266
PubMedCentral® Posted Date
3-3-2022
PubMedCentral® Full Text Version
Post-print
Correction
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Genetics Commons, Oncology Commons
Comments
This article has been corrected. See Nat Med. 2022 Apr 28;28(5):1097.