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- Title
Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia.
- Authors
Zhai, Yanan; Singh, Prashant; Dolnik, Anna; Brazda, Peter; Atlasy, Nader; del Gaudio, Nunzio; Döhner, Konstanze; Döhner, Hartmut; Minucci, Saverio; Martens, Joost; Altucci, Lucia; Megchelenbrink, Wout; Bullinger, Lars; Stunnenberg, Hendrik G.
- Abstract
Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts in the hematopoietic system. The heterogeneity and evolution of cancer blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. In this study, we investigated the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs at genetic and transcriptional levels, and unveiled the underlying pathways and genes contributing to recurrence. Methods: Whole-exome sequencing was used to detect somatic mutations and large copy number variations (CNVs). Single cell RNA-seq was performed to investigate the clonal heterogeneity between Dx-Re pairs and amongst patients. Results: scRNA-seq analysis revealed extensive expression differences between patients and Dx-Re pairs, even for those with the same -presumed- initiating events. Transcriptional differences between and within patients are associated with clonal composition and evolution, with the most striking differences in patients that gained large-scale copy number variations at relapse. These differences appear to have significant molecular implications, exemplified by a DNMT3A/FLT3-ITD patient where the leukemia switched from an AP-1 regulated clone at Dx to a mTOR signaling driven clone at Re. The two distinct AML1-ETO pairs share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells evolved from the Dx cells. Conclusions: In summary, the single cell RNA data underpinned the tumor heterogeneity not only amongst patient blasts with similar initiating mutations but also between each Dx-Re pair. Our results suggest alternatively and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence.
- Subjects
ACUTE myeloid leukemia; HEMATOPOIETIC stem cells; SOMATIC mutation; PRELEUKEMIA; HEMATOPOIETIC system; CELL migration
- Publication
Molecular Cancer, 2022, Vol 21, Issue 1, p1
- ISSN
1476-4598
- Publication type
Article
- DOI
10.1186/s12943-022-01635-4