期刊
LEUKEMIA
卷 36, 期 11, 页码 2678-2689出版社
SPRINGERNATURE
DOI: 10.1038/s41375-022-01686-y
关键词
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资金
- Faculty of Health Sciences Divisional Scholarship, University of Adelaide
- Dawes Top up Scholarship, Royal Adelaide Hospital, South Australia Health and Medical Research Institute
- National Health and Medical Research Council Medical Research Future Fund (MRFF) Investigator Grant [APP1195517]
- Cancer Australia [APP2013617]
- Leukemia Foundation of Australia
- National Health and Medical Research Council [APP2007739, APP1182564, APP 2004288]
- Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility
- ACRF Discovery Accelerator, a Commonwealth Serum Laboratories Centenary Fellowship
- Hospital Research Fund
- Australian Medical Research Future Fund for Rare Diseases, Rare Cancers and Unmet Need
- CAUL
- Leukemia & Lymphoma Society Translational Research Program
This study characterized the microenvironment of therapy-related myeloid neoplasms (tMN) using a multiomic approach. The results showed that bone marrow stromal cells in tMN patients exhibited a senescent phenotype with increased metabolic activity and secretion of pro-inflammatory cytokines, leading to inhibition of adipogenesis. Importantly, senescence phenotypes were induced months before the onset of secondary cancer. These findings highlight the role of senescence in the pathogenesis of tMN and provide valuable insights for future therapeutic strategies.
Therapy-related myeloid neoplasm (tMN) is considered a direct consequence of DNA damage in hematopoietic stem cells. Despite increasing recognition that altered stroma can also drive leukemogenesis, the functional biology of the tMN microenvironment remains unknown. We performed multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterization of bone marrow stromal cells from tMN patients. Critically, we also compared (i) patients with myeloid neoplasm and another cancer but without cytotoxic exposure, (ii) typical primary myeloid neoplasm, and (iii) age-matched controls to decipher the microenvironmental changes induced by cytotoxics vs. neoplasia. Strikingly, tMN exhibited a profoundly senescent phenotype with induction of CDKN1A and beta-Galactosidase, defective phenotype, and proliferation. Moreover, tMN stroma showed delayed DNA repair and defective adipogenesis. Despite their dormant state, tMN stromal cells were metabolically highly active with a switch toward glycolysis and secreted multiple pro-inflammatory cytokines indicative of a senescent-secretory phenotype that inhibited adipogenesis. Critically, senolytics not only eliminated dormant cells, but also restored adipogenesis. Finally, sequential patient sampling showed senescence phenotypes are induced within months of cytotoxic exposure, well prior to the onset of secondary cancer. Our data underscores a role of senescence in the pathogenesis of tMN and provide a valuable resource for future therapeutics.
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