Integrated single-cell transcriptome analysis of CD34 + enriched leukemic stem cells revealed intra- and inter-patient transcriptional heterogeneity in pediatric acute myeloid leukemia
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature..
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 LSC-enriched 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:102 |
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| Enthalten in: |
Annals of hematology - 102(2023), 1 vom: 17. Jan., Seite 73-87 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Thakral, Deepshi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.01.2023 Date Revised 11.01.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00277-022-05021-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM350392951 |
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| 100 | 1 | |a Thakral, Deepshi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Integrated single-cell transcriptome analysis of CD34 + enriched leukemic stem cells revealed intra- and inter-patient transcriptional heterogeneity in pediatric acute myeloid leukemia |
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| 520 | |a 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 LSC-enriched 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acute myeloid leukemia | |
| 650 | 4 | |a DEGs | |
| 650 | 4 | |a Gene expression profile | |
| 650 | 4 | |a Leukemic stem cells | |
| 650 | 4 | |a Pediatric AML | |
| 650 | 4 | |a Single-cell sequencing | |
| 650 | 4 | |a Transcriptional heterogeneity | |
| 650 | 7 | |a Antigens, CD34 |2 NLM | |
| 650 | 7 | |a LPAR6 protein, human |2 NLM | |
| 650 | 7 | |a Receptors, Lysophosphatidic Acid |2 NLM | |
| 700 | 1 | |a Singh, Vivek Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Ritu |e verfasserin |4 aut | |
| 700 | 1 | |a Jha, Nitu |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Aafreen |e verfasserin |4 aut | |
| 700 | 1 | |a Kaur, Gurvinder |e verfasserin |4 aut | |
| 700 | 1 | |a Rai, Sandeep |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Vijay |e verfasserin |4 aut | |
| 700 | 1 | |a Supriya, Manisha |e verfasserin |4 aut | |
| 700 | 1 | |a Bakhshi, Sameer |e verfasserin |4 aut | |
| 700 | 1 | |a Seth, Rachna |e verfasserin |4 aut | |
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