Repository logo
 

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

Published version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Zhai, Yanan 
Singh, Prashant 
Dolnik, Anna 
Brazda, Peter 
Atlasy, Nader 

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.

Description

Keywords

Acute myeloid Leukemia, Genome analysis, Leukemic stem cells, Recurrence, Single-cell RNA sequencing, DNA Copy Number Variations, Humans, Leukemia, Myeloid, Acute, Mutation, Recurrence, Single-Cell Analysis, Transcriptome, fms-Like Tyrosine Kinase 3

Journal Title

Mol Cancer

Conference Name

Journal ISSN

1476-4598
1476-4598

Volume Title

21

Publisher

Springer Science and Business Media LLC