In:
PLOS Biology, Public Library of Science (PLoS), Vol. 21, No. 5 ( 2023-5-2), p. e3002088-
Abstract:
Leukemogenesis is proposed to be a multistep process by which normal hematopoietic stem and progenitor cells are transformed into full-blown leukemic cells, the details of which are not fully understood. Here, we performed serial single-cell transcriptome analyses of preleukemic and leukemic cells (PLCs) and constructed the cellular and molecular transformation trajectory in a Myc -driven acute myeloid leukemia (AML) model in mice, which represented the transformation course in patients. We found that the Myc targets were gradually up-regulated along the trajectory. Among them were splicing factors, which showed stage-specific prognosis for AML patients. Furthermore, we dissected the detailed gene network of a tipping point for hematopoietic stem and progenitor cells (HSPCs) to generate initiating PLCs, which was characterized by dramatically increased splicing factors and unusual RNA velocity. In the late stage, PLCs acquired explosive heterogeneity through RNA alternative splicing. Among them, the Hsp90aa1 hi subpopulation was conserved in both human and mouse AML and associated with poor prognosis. Exon 4 skipping of Tmem134 was identified in these cells. While the exon skipping product Tmem134β promoted the cell cycle, full-length Tmem134α delayed tumorigenesis. Our study emphasized the critical roles of RNA splicing in the full process of leukemogenesis.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3002088
DOI:
10.1371/journal.pbio.3002088.g001
DOI:
10.1371/journal.pbio.3002088.g002
DOI:
10.1371/journal.pbio.3002088.g003
DOI:
10.1371/journal.pbio.3002088.g004
DOI:
10.1371/journal.pbio.3002088.g005
DOI:
10.1371/journal.pbio.3002088.g006
DOI:
10.1371/journal.pbio.3002088.s001
DOI:
10.1371/journal.pbio.3002088.s002
DOI:
10.1371/journal.pbio.3002088.s003
DOI:
10.1371/journal.pbio.3002088.s004
DOI:
10.1371/journal.pbio.3002088.s005
DOI:
10.1371/journal.pbio.3002088.s006
DOI:
10.1371/journal.pbio.3002088.s007
DOI:
10.1371/journal.pbio.3002088.s008
DOI:
10.1371/journal.pbio.3002088.s009
DOI:
10.1371/journal.pbio.3002088.s010
DOI:
10.1371/journal.pbio.3002088.s011
DOI:
10.1371/journal.pbio.3002088.s012
DOI:
10.1371/journal.pbio.3002088.s013
DOI:
10.1371/journal.pbio.3002088.s014
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2126773-X
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