Title | Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Cortés-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 |
Journal | Cell Stem Cell |
Volume | 30 |
Issue | 9 |
Pagination | 1262-1281.e8 |
Date Published | 2023 Sep 07 |
ISSN | 1875-9777 |
Keywords | Humans, 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. |
DOI | 10.1016/j.stem.2023.07.012 |
Alternate Journal | Cell Stem Cell |
PubMed ID | 37582363 |
PubMed Central ID | PMC10528176 |
Grant List | R33 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 |
Submitted by bel2021 on February 16, 2024 - 10:37am