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Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq
- Source :
- Leukemia
- Publication Year :
- 2020
-
Abstract
- Hematopoiesis is hierarchical, and it has been postulated that acute myeloid leukemia (AML) is organized similarly with leukemia stem cells (LSCs) residing at the apex. Limited cells acquired by fluorescence activated cell sorting in tandem with targeted amplicon-based sequencing (LC-FACSeq) enables identification of mutations in small subpopulations of cells, such as LSCs. Leveraging this, we studied clonal compositions of immunophenotypically-defined compartments in AML through genomic and functional analyses at diagnosis, remission and relapse in 88 AML patients. Mutations involving DNA methylation pathways, transcription factors and spliceosomal machinery did not differ across compartments, while signaling pathway mutations were less frequent in putative LSCs. We also provide insights into TP53-mutated AML by demonstrating stepwise acquisition of mutations beginning from the preleukemic hematopoietic stem cell stage. In 10 analyzed cases, acquisition of additional mutations and del(17p) led to genetic and functional heterogeneity within the LSC pool with subclones harboring varying degrees of clonogenic potential. Finally, we use LC-FACSeq to track clonal evolution in serial samples, which can also be a powerful tool to direct targeted therapy against measurable residual disease. Therefore, studying clinically significant small subpopulations of cells can improve our understanding of AML biology and offers advantages over bulk sequencing to monitor the evolution of disease.
- Subjects :
- 0301 basic medicine
Adult
Male
Cancer Research
Biology
Somatic evolution in cancer
Article
Acute myeloid leukaemia
Immunophenotyping
Clonal Evolution
03 medical and health sciences
Young Adult
0302 clinical medicine
medicine
Biomarkers, Tumor
Humans
Cancer genetics
Aged
Aged, 80 and over
Myeloid leukemia
Hematopoietic stem cell
Correction
Hematology
Genomics
Amplicon
Middle Aged
medicine.disease
Flow Cytometry
Hematopoietic Stem Cells
Prognosis
Haematopoiesis
Leukemia
Leukemia, Myeloid, Acute
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
DNA methylation
Mutation
Cancer research
Neoplastic Stem Cells
Female
Stem cell
Follow-Up Studies
Subjects
Details
- ISSN :
- 14765551
- Volume :
- 35
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....7a7eae162980dfd0939ef606772acafd