@article{e918aa2d64824025a2e8d46c92ebe4ec,
title = "Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells",
abstract = "Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations and mis-splicing fuel therapy-resistant leukemia stem cell (LSC) generation in adults, splicing deregulation has not been extensively studied in pAML. Herein, we describe single-cell proteogenomics analyses, transcriptome-wide analyses of FACS-purified hematopoietic stem and progenitor cells followed by differential splicing analyses, dual-fluorescence lentiviral splicing reporter assays, and the potential of a selective splicing modulator, Rebecsinib, in pAML. Using these methods, we discover transcriptomic splicing deregulation typified by differential exon usage. In addition, we discover downregulation of splicing regulator RBFOX2 and CD47 splice isoform upregulation. Importantly, splicing deregulation in pAML induces a therapeutic vulnerability to Rebecsinib in survival, self-renewal, and lentiviral splicing reporter assays. Taken together, the detection and targeting of splicing deregulation represent a potentially clinically tractable strategy for pAML therapy.",
keywords = "CD47, RBFOX2, SF3B1, embryonic stem cells, hematopoietic stem cells, pediatric AML, pre-mRNA splicing, splicing modulation",
author = "G.J.L. Kaspers and {van der Werf}, Inge and Mondala, {Phoebe K.} and Steel, {S. Kathleen} and Larisa Balaian and Luisa Ladel and Mason, {Cayla N.} and Diep, {Raymond H.} and Jessica Pham and Jacqueline Cloos and Chan, {Warren C.} and Adam Mark and {la Clair}, {James J.} and Peggy Wentworth and Fisch, {Kathleen M.} and Crews, {Leslie A.} and Whisenant, {Thomas C.} and Burkart, {Michael D.} and Donohoe, {Mary E.} and Jamieson, {Catriona H. M.}",
note = "Funding Information: We would like to thank our funding agencies for their vital support, including Padres Pedal the Cause, NIH/NCI R01CA205944, NIH/NIDDK R01DK114468-01, NIH/NCI 2P30CA023100-28, CIRM TRAN1-10540, MPN Research Foundation, LLS Blood Cancer Discoveries, NIH/NCATS UL1TR001442, and NASA NRA NNJ13ZBG001N. Also, we would like to thank the Moores Family Foundation, the Koman Family Foundation, the Sanford Stem Cell Institute, and the UC San Diego Moores Cancer Center for their generous support. I.v.d.W. was supported by the Diamond Program of the Graduate Oncology School Amsterdam, and C.H.M.J. is supported by the Koman Family Presidential Endowed Chair for Cancer Research. I.v.d.W. P.K.M. S.K.S. L.L. C.N.M. and C.H.M.J. designed research, performed experiments, and analyzed the data. R.H.D. engineered the lentiviral dual-fluorescence splicing reporter. J.C. G.J.L.K. P.W. and L.A.C. supported study design. T.C.W. performed all computational analyses related to RNA-seq differential expression, differential splicing, network generation, and single-cell data. T.C.W. and A.M. performed the RNA editing analysis of the RNA-seq data. K.M.F. supervised the bioinformatic analysis. W.C.C. J.J.L.C. and M.D.B. synthesized and prepared splicing modulatory drugs. M.E.D. designed and performed the single-cell immunophenotyping. C.H.M.J. designed the study and supervised the analysis. I.v.d.W. M.E.D. S.K.S. and C.H.M.J. wrote the manuscript. M.D.B. is a co-founder of Aspera Biomedicines. C.H.M.J. is a co-founder of Aspera Biomedicines and Impact Biomedicines and has received royalties for intellectual property licensed by Forty Seven Inc. We support inclusive, diverse, and equitable conduct of research. Funding Information: We would like to thank our funding agencies for their vital support, including Padres Pedal the Cause, NIH /NCI R01CA205944 , NIH /NIDDK R01DK114468-01 , NIH /NCI 2P30CA023100-28 , CIRM TRAN1-10540 , MPN Research Foundation , LLS Blood Cancer Discoveries, NIH /NCATS UL1TR001442 , and NASA NRA NNJ13ZBG001N . Also, we would like to thank the Moores Family Foundation , the Koman Family Foundation , the Sanford Stem Cell Institute , and the UC San Diego Moores Cancer Center for their generous support. I.v.d.W. was supported by the Diamond Program of the Graduate Oncology School Amsterdam, and C.H.M.J. is supported by the Koman Family Presidential Endowed Chair for Cancer Research. Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = mar,
day = "21",
doi = "https://doi.org/10.1016/j.xcrm.2023.100962",
language = "English",
volume = "4",
pages = "100962",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}