Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths.

TitleSingle-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths.
Publication TypeJournal Article
Year of Publication2023
AuthorsCortés-López M, Chamely P, Hawkins AG, Stanley RF, Swett AD, Ganesan S, Mouhieddine TH, Dai X, Kluegel L, Chen C, Batta K, Furer N, Vedula RS, Beaulaurier J, Drong AW, Hickey S, Dusaj N, Mullokandov G, Stasiw AM, Su J, Chaligne R, Juul S, Harrington E, Knowles DA, Potenski CJ, Wiseman DH, Tanay A, Shlush L, Lindsley RC, Ghobrial IM, Taylor J, Abdel-Wahab O, Gaiti F, Landau DA
JournalCell Stem Cell
Volume30
Issue9
Pagination1262-1281.e8
Date Published2023 Sep 07
ISSN1875-9777
KeywordsHumans, Multiomics, Mutation, Myelodysplastic Syndromes, Phosphoproteins, RNA Splice Sites, RNA Splicing, RNA Splicing Factors
Abstract

RNA splicing factors are recurrently mutated in clonal blood disorders, but the impact of dysregulated splicing in hematopoiesis remains unclear. To overcome technical limitations, we integrated genotyping of transcriptomes (GoT) with long-read single-cell transcriptomics and proteogenomics for single-cell profiling of transcriptomes, surface proteins, somatic mutations, and RNA splicing (GoT-Splice). We applied GoT-Splice to hematopoietic progenitors from myelodysplastic syndrome (MDS) patients with mutations in the core splicing factor SF3B1. SF3B1mut cells were enriched in the megakaryocytic-erythroid lineage, with expansion of SF3B1mut erythroid progenitor cells. We uncovered distinct cryptic 3' splice site usage in different progenitor populations and stage-specific aberrant splicing during erythroid differentiation. Profiling SF3B1-mutated clonal hematopoiesis samples revealed that erythroid bias and cell-type-specific cryptic 3' splice site usage in SF3B1mut cells precede overt MDS. Collectively, GoT-Splice defines the cell-type-specific impact of somatic mutations on RNA splicing, from early clonal outgrowths to overt neoplasia, directly in human samples.

DOI10.1016/j.stem.2023.07.012
Alternate JournalCell Stem Cell
PubMed ID37582363
PubMed Central IDPMC10528176
Grant ListR33 CA267219 / CA / NCI NIH HHS / United States
UG3 NS132139 / NS / NINDS NIH HHS / United States
RM1 HG011014 / HG / NHGRI NIH HHS / United States
R01 HL128239 / HL / NHLBI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 HL157387 / HL / NHLBI NIH HHS / United States
R01 CA251138 / CA / NCI NIH HHS / United States
R01 CA242020 / CA / NCI NIH HHS / United States
F30 HL156496 / HL / NHLBI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States

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