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Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells

Inge van der Werf, Phoebe K Mondala, S Kathleen Steel, Larisa Balaian, Luisa Ladel, Cayla N Mason, Raymond H Diep, Jessica Pham, Jacqueline Cloos, Gertjan J L Kaspers, Warren C Chan, Adam Mark, James J La Clair, Peggy Wentworth, Kathleen M Fisch, Leslie A Crews, Thomas C Whisenant, Michael D Burkart, Mary E Donohoe, Catriona H M Jamieson
Cell Reports Medicine Mar 2023

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.




Institution Type


Indication / Modality

Acute Myleoid Leukemia, Acute Myleoid Leukemia (AML)

Goal of Study

Clinical Profiling

PAD Project


Analytes Assessed

Extracellular Protein, InDels, SNV



Proof Point Demonstrated

Clonality, Co-occurrence, Multi-omics