Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq
| Autor: | Tzyy-Jye Doong, Nicole Grieselhuber, Nyla A. Heerema, Gerard Lozanski, Cecelia R. Miller, Karilyn Larkin, Tierney Kauffman, Rosa Lapalombella, Arletta Lozanski, John C. Byrd, Clara D. Bloomfield, Casey Cempre, Shelley Orwick, Bhavana Bhatnagar, Alice S. Mims, Lynne V. Abruzzo, Gregory K. Behbehani, Eileen Hu, Virginia M. Goettl, Alison Walker, Steven Sher, Pu Zhang, Caner Saygin, Jordan N. Skinner, James S. Blachly, Jadwiga Labanowska, Deedra Nicolet |
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| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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