Journal
ANNALS OF HEMATOLOGY
Volume 102, Issue 1, Pages 73-87Publisher
SPRINGER
DOI: 10.1007/s00277-022-05021-4
Keywords
Acute myeloid leukemia; Pediatric AML; Leukemic stem cells; Gene expression profile; Single-cell sequencing; Transcriptional heterogeneity; DEGs
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Single-cell sequencing was used to investigate the transcriptional heterogeneity of CD34 + enriched leukemic stem cells in pediatric AML. The study identified unique leukemic stem cell clusters for each patient and revealed intra-patient heterogeneity. Gene expression analysis showed upregulation of genes involved in non-coding RNA processing, ribonucleoprotein assembly, apoptotic processes, cytokine stimulus response, and negative regulation of transcription in LSC-enriched clusters. Validation confirmed the upregulation of specific genes and kinases in LSC-enriched clusters, which correlated with MRD status and survival outcomes. These findings highlight the diversity and potential therapeutic targets of AML LSC.
To gain insights into the idiosyncrasies of CD34 + enriched leukemic stem cells, we investigated the nature and extent of transcriptional heterogeneity by single-cell sequencing in pediatric AML. Whole transcriptome analysis of 28,029 AML single cells was performed using the nanowell cartridge-based barcoding technology. Integrated transcriptional analysis identified unique leukemic stem cell clusters of each patient and intra-patient heterogeneity was revealed by multiple LSCenriched clusters differing in their cell cycle processes and BCL2 expression. All LSC-enriched clusters exhibited gene expression profile of dormancy and self-renewal. Upregulation of genes involved in non-coding RNA processing and ribonucleoprotein assembly were observed in LSC-enriched clusters relative to HSC. The genes involved in regulation of apoptotic processes, response to cytokine stimulus, and negative regulation of transcription were upregulated in LSC-enriched clusters as compared to the blasts. Validation of top altered genes in LSC-enriched clusters confirmed upregulation of TCF7L2, JUP, ARHGAP25, LPAR6, and PRDX1 genes, and serine/threonine kinases (STK24, STK26). Upregulation of LPAR6 showed trend towards MRD positive status (Odds ratio = 0.126; 95% CI = 0.0144-1.10; p = 0.067) and increased expression of STK26 significantly correlated with higher RFS (HR = 0.231; 95% CI = 0.0506-1.052; p = 0.04). Our findings addressed the inter and intra-patient diversity within AML LSC and potential signaling and chemoresistance-associated targets that warrant investigation in larger cohort that may guide precision medicine in the near future.
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