TY - JOUR
T1 - Genetic and Transcriptional Contributions to Relapse in Normal Karyotype Acute Myeloid Leukemia
AU - Petti, Allegra A.
AU - Khan, Saad M.
AU - Xu, Ziheng
AU - Helton, Nichole
AU - Fronick, Catrina C.
AU - Fulton, Robert
AU - Ramakrishnan, Sai M.
AU - Srivatsan, Sridhar Nonavinkere
AU - Heath, Sharon E.
AU - Westervelt, Peter
AU - Payton, Jacqueline E.
AU - Walter, Matthew J.
AU - Link, Daniel C.
AU - DiPersio, John
AU - Miller, Christopher
AU - Ley, Timothy J.
N1 - Publisher Copyright:
© American Association for Cancer Research Inc.. All Rights Reserved.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - To better understand clonal and transcriptional adaptations after relapse in patients with acute myeloid leukemia (AML), we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole-genome sequencing to characterize clonal evolution, and deep-coverage single-cell RNA sequencing on the same samples, which yielded 142,642 high-quality cells for analysis. Identifying expressed mutations in individual cells enabled us to discriminate between normal and AML cells, to identify coordinated changes in the genome and transcriptome, and to identify subclone-specific cell states. We quantified the coevolution of genetic and transcriptional heterogeneity during AML progression, and found that transcriptional changes were significantly correlated with genetic changes. However, transcriptional adaptation sometimes occurred independently, suggesting that clonal evolution does not represent all relevant biological changes. In three cases, we identified cells at diagnosis that likely seeded the relapse. Finally, these data revealed a conserved relapse-enriched leukemic cell state bearing markers of stemness, quiescence, and adhesion.
AB - To better understand clonal and transcriptional adaptations after relapse in patients with acute myeloid leukemia (AML), we collected presentation and relapse samples from six normal karyotype AML cases. We performed enhanced whole-genome sequencing to characterize clonal evolution, and deep-coverage single-cell RNA sequencing on the same samples, which yielded 142,642 high-quality cells for analysis. Identifying expressed mutations in individual cells enabled us to discriminate between normal and AML cells, to identify coordinated changes in the genome and transcriptome, and to identify subclone-specific cell states. We quantified the coevolution of genetic and transcriptional heterogeneity during AML progression, and found that transcriptional changes were significantly correlated with genetic changes. However, transcriptional adaptation sometimes occurred independently, suggesting that clonal evolution does not represent all relevant biological changes. In three cases, we identified cells at diagnosis that likely seeded the relapse. Finally, these data revealed a conserved relapse-enriched leukemic cell state bearing markers of stemness, quiescence, and adhesion.
UR - http://www.scopus.com/inward/record.url?scp=85126708326&partnerID=8YFLogxK
U2 - 10.1158/2643-3230.BCD-21-0050
DO - 10.1158/2643-3230.BCD-21-0050
M3 - Article
C2 - 35019859
AN - SCOPUS:85126708326
SN - 2643-3230
VL - 3
SP - 32
EP - 49
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 1
ER -