Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia

Yanan Zhai, Prashant Singh, Anna Dolnik, Peter Brázda, Peter Atlasy, Nunzio de Gaudio, Konstanze Döhner, Hartmut Dohner, Saverio Minucci, Joost H A Martens, Lucia Altucci, Wout Megchelenbrink, Lars Bullinger, Henk Stunnenberg

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournalMolecular cancer
Publication statusPublished - 19 Aug 2022

Keywords

  • Acute myeloid Leukemia
  • Single-cell RNA sequencing
  • Recurrence
  • Leukemic stem cells
  • Genome analysis

Fingerprint

Dive into the research topics of 'Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia'. Together they form a unique fingerprint.

Cite this