TY - JOUR
T1 - Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths
AU - Cortés-López, Mariela
AU - Chamely, Paulina
AU - Hawkins, Allegra G.
AU - Stanley, Robert F.
AU - Swett, Ariel D.
AU - Ganesan, Saravanan
AU - Mouhieddine, Tarek H.
AU - Dai, Xiaoguang
AU - Kluegel, Lloyd
AU - Chen, Celine
AU - Batta, Kiran
AU - Furer, Nili
AU - Vedula, Rahul S.
AU - Beaulaurier, John
AU - Drong, Alexander W.
AU - Hickey, Scott
AU - Dusaj, Neville
AU - Mullokandov, Gavriel
AU - Stasiw, Adam M.
AU - Su, Jiayu
AU - Chaligné, Ronan
AU - Juul, Sissel
AU - Harrington, Eoghan
AU - Knowles, David A.
AU - Potenski, Catherine J.
AU - Wiseman, Daniel H.
AU - Tanay, Amos
AU - Shlush, Liran
AU - Lindsley, Robert C.
AU - Ghobrial, Irene M.
AU - Taylor, Justin
AU - Abdel-Wahab, Omar
AU - Gaiti, Federico
AU - Landau, Dan A.
PY - 2023/9/7
Y1 - 2023/9/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85169010948&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2023.07.012
DO - 10.1016/j.stem.2023.07.012
M3 - Article
C2 - 37582363
AN - SCOPUS:85169010948
SN - 1934-5909
VL - 30
SP - 1262-1281.e8
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 9
ER -