2. Academic Validation
  3. Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML

Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML

  • Genome Biol. 2023 Aug 31;24(1):199. doi: 10.1186/s13059-023-03031-7.
Yongping Zhang # 1,  Shuting Jiang # 2 3,  Fuhong He # 2 3,  Yuanyuan Tian # 1,  Haiyang Hu 2 3,  Li Gao 1,  Lin Zhang 2 3,  Aili Chen 2 3,  Yixin Hu 1,  Liyan Fan 1,  Chun Yang 4,  Bi Zhou 5,  Dan Liu 2,  Zihan Zhou 2 3,  Yanxun Su 2 3,  Lei Qin 2 3,  Yi Wang 1,  Hailong He 1,  Jun Lu 1,  Peifang Xiao 1,  Shaoyan Hu 6,  Qian-Fei Wang 7 8
Affiliations

Affiliations

  • 1 Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215025, China.
  • 2 CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215025, China.
  • 5 SuZhou Hospital of Anhui Medical University, Suzhou, China.
  • 6 Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215025, China. [email protected].
  • 7 CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. [email protected].
  • 8 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • # Contributed equally.
PMID: 37653425 DOI: 10.1186/s13059-023-03031-7
Abstract

Background: Cancer patients can achieve dramatic responses to chemotherapy yet retain resistant tumor cells, which ultimately results in relapse. Although xenograft model studies have identified several cellular and molecular features that are associated with chemoresistance in acute myeloid leukemia (AML), to what extent AML patients exhibit these properties remains largely unknown.

Results: We apply single-cell RNA sequencing to paired pre- and post-chemotherapy whole bone marrow samples obtained from 13 pediatric AML patients who had achieved disease remission, and distinguish AML clusters from normal cells based on their unique transcriptomic profiles. Approximately 50% of leukemic stem and progenitor populations actively express leukemia stem cell (LSC) and oxidative phosphorylation (OXPHOS) signatures, respectively. These clusters have a higher chance of tolerating therapy and exhibit an enhanced metabolic program in response to treatment. Interestingly, the transmembrane receptor CD69 is highly expressed in chemoresistant hematopoietic stem cell (HSC)-like populations (named the CD69+ HSC-like subpopulation). Furthermore, overexpression of CD69 results in suppression of the mTOR signaling pathway and promotion of cell quiescence and adhesion in vitro. Finally, the presence of CD69+ HSC-like cells is associated with unfavorable genetic mutations, the persistence of residual tumor cells in chemotherapy, and poor outcomes in independent pediatric and adult public AML cohorts.

Conclusions: Our analysis reveals leukemia stem cell and OXPHOS as two major chemoresistant features in human AML patients. CD69 may serve as a potential biomarker in defining a subpopulation of chemoresistant leukemia stem cells. These findings have important implications for targeting residual chemo-surviving AML cells.

Keywords

AML; CD69; Chemotherapy resistance; HSC-like; Leukemia stem cell; Oxidative phosphorylation; Residual tumor cell; Single-cell RNA sequencing.

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