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

被引：26

作者：

Cortes-Lopez, Mariela

Chamely, Paulina

Hawkins, Allegra G. ^{[3
]}

Stanley, Robert F.

Swett, Ariel D.

Ganesan, Saravanan

Mouhieddine, Tarek H.

Dai, Xiaoguang

Kluegel, Lloyd

Chen, Celine ^{[7
]}

Batta, Kiran ^{[8
]}

Furer, Nili ^{[9
]}

Vedula, Rahul S. ^{[5
]}

Beaulaurier, John ^{[10
]}

Drong, Alexander W. ^{[6
]}

Hickey, Scott ^{[10
]}

Dusaj, Neville ^{[1
,2
,7
]}

Mullokandov, Gavriel ^{[1
,2
]}

Stasiw, Adam M. ^{[1
,2
]}

Su, Jiayu ^{[1
,11
]}

Chaligne, Ronan ^{[1
,2
,12
]}

Juul, Sissel ^{[6
]}

Harrington, Eoghan ^{[6
]}

Knowles, David A. ^{[1
,11
,13
]}

Potenski, Catherine J. ^{[1
,2
]}

Wiseman, Daniel H. ^{[8
]}

Tanay, Amos ^{[1
,4
,14
]}

Shlush, Liran ^{[9
]}

Lindsley, Robert C. ^{[5
]}

Ghobrial, Irene M. ^{[5
]}

Taylor, Justin ^{[1
,5
,15
]}

Abdel-Wahab, Omar ^{[4
]}

Gaiti, Federico ^{[1
,6
,16
,17
]}

Landau, Dan A. ^{[1
,2
,18
]}

机构：

[1] New York Genome Ctr, New York, NY 10013 USA

[2] Weill Cornell Med, Dept Med, Div Hematol & Med Oncol, New York, NY 10065 USA

[3] Alexs Lemonade Stand Fdn, Childhood Canc Data Lab, Philadelphia, PA USA

[4] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, New York, NY USA

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA

[6] Oxford Nanopore Technol Inc, New York, NY 10013 USA

[7] Rockefeller Univ, Weill Cornell Med, Mem Sloan Kettering Canc Ctr, Triinst MD PhD Program, New York, NY USA

[8] Univ Manchester, Div Canc Sci, Manchester, England

[9] Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel

[10] Oxford Nanopore Technol Inc, San Francisco, CA USA

[11] Columbia Univ, Dept Syst Biol, New York, NY USA

[12] Mem Sloan Kettering Canc Ctr, Computat & Syst Biol Program, New York, NY 10021 USA

[13] Columbia Univ, Dept Comp Sci, New York, NY USA

[14] Weizmann Inst Sci, Dept Comp Sci & Appl Math, Rehovot, Israel

[15] Univ Miami, Sylvester Comprehens Canc Ctr, Miller Sch Med, Miami, FL USA

[16] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[17] Univ Toronto, Med Biophys, Toronto, ON, Canada

[18] Weill Cornell Med, Inst Computat Biomed, New York, NY 10065 USA

来源：

CELL STEM CELL | 2023年 / 30卷 / 09期

关键词：

STEM-CELLS; SOMATIC MUTATIONS; ERYTHROID MATURATION; SF3B1; MUTATION; P53; EXPRESSION; CANCER; GENE; IDENTIFICATION; CONSEQUENCES;

D O I：

10.1016/j.stem.2023.07.012

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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 30 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 30 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.

引用

页码：1262 / +

页数：29

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