<p>This study evaluates the gene expression and splicing changes between pediatric patients with and without Acute Myeloid Leukemia (AML) and pediatric and adult patients with AML. We obtained bone marrow or peripheral blood from patients and isolated CD34+ stem and/or progenitor cells from pediatric patients with AML (10) or without AML (6) and adult patients with AML (5). In parallel, a targeted analysis for known, deleterious, genetic mutations in the <a href="https://www.ncbi.nlm.nih.gov/gene/3845">KRAS</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/4893">NRAS</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/58508">KMT2C</a> genes identified 2, 5, and 6 AML patients with alterations, respectively. Additionally, Tapestri analysis further identified a mutation in the intronic region of the <a href="https://www.ncbi.nlm.nih.gov/gene/23451">SF3B1</a> gene in multiple pediatric AML patients. RNA-Seq was performed on the purified cell populations at The Scripps Research Institute Next Generation Core on an Illumina NextSeq 500 sequencer with 150bp paired-end reads.</p><p>These datasets revealed that, similar to adult AML, pediatric AML samples were enriched for Leukemia Stem Cells (LSC) markers. A deeper analysis showed widespread dysregulation of splicing in pediatric AML samples compared to age-matched non-leukemic samples. In addition, the splicing regulator <a href="https://www.ncbi.nlm.nih.gov/gene/23543">RBFOX2</a> was downregulated with an accompanying increase in specific <a href="https://www.ncbi.nlm.nih.gov/gene/961">CD47</a> splice isoforms in the pediatric AML samples. Thus, the increased presence of LSCs in pediatric AML is possibly driven by global splicing deregulation, and the treatment with splicing modulators like Rebecsinib has a potential therapeutic value for eradicating LSCs in these patients.</p>

Detection and Targeting of Splicing Deregulation in Pediatric Acute Myeloid Leukemia Stem Cells

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