Distinct Patterns of Clonal Evolution Drive Myelodysplastic Syndrome Progression to Secondary Acute Myeloid Leukemia

Details

• Personal Author:
  Bhat P ; Brooks A ; Cartailler JA ; Cartailler J-P ; Ferrell PB Jr. ; Guess T ; Holt C ; Potts CR ; Savona MR ; Wheeler FC ; Yenamandra A
• Description:
  Clonal evolution in myelodysplastic syndrome (MDS) can result in clinical progression and secondary acute myeloid leukemia (sAML). To dissect changes in clonal architecture associated with this progression, we performed single-cell genotyping of paired MDS and sAML samples from 18 patients. Analysis of single-cell genotypes revealed patient-specific clonal evolution and enabled the assessment of single-cell mutational cooccurrence. We discovered that changes in clonal architecture proceed via distinct patterns, classified as static or dynamic, with dynamic clonal architectures having a more proliferative phenotype by blast count fold change. Proteogenomic analysis of a subset of patients confirmed that pathogenic mutations were primarily confined to primitive and mature myeloid cells, though we also identify rare but present mutations in lymphocyte subsets. Single-cell transcriptomic analysis of paired sample sets further identified gene sets and signaling pathways involved in two cases of progression. Together, these data define serial changes in the MDS clonal landscape with clinical and therapeutic implications. Significance: Precise clonal trajectories in MDS progression are made possible by single-cell genomic sequencing. Here we use this technology to uncover the patterns of clonal architecture and clonal evolution that drive the transformation to secondary AML. We further define the phenotypic and transcriptional changes of disease progression at the single-cell level. [Description provided by NIOSH]
• Subjects:
  Blood Genetics Neoplasms Occupational Health Safety
• Keywords:
  Blood Cells Cancer Cell Alteration Cell Signaling DNA Damage Genes Genetic Factors Lymphocytes Mutation Myeloid Tissue
• ISSN:
  2643-3230
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  New York ; OSHA Region 2 ; OSHA Region 4 ; Tennessee
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  316-329
• Volume:
  3
• Issue:
  4
• NIOSHTIC Number:
  nn:20065978
• Citation:
  Blood Cancer Discov 2022 Jul; 3(4):316-329
• Contact Point Address:
  P. Brent Ferrell Jr, Vanderbilt University Medical Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232
• Email:
  brent.ferrell@vumc.org
• Federal Fiscal Year:
  2022
• Performing Organization:
  Albert Einstein College of Medicine, Bronx, New York
• Peer Reviewed:
  True
• Start Date:
  20210701
• Source Full Name:
  Blood Cancer Discovery
• End Date:
  20240630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:024893155154ee2944f35c2e58eeef339cceef7f0a9202b9657fffd288e8da47fcdb9c87cdc8c8dd898dceb57f6189333762adbed3932605148797ee5774a5d0
• Download URL:
  https://stacks.cdc.gov/view/cdc/209071/cdc_209071_DS1.pdf
• File Type:
  [PDF - 8.03 MB ]