The IRAK4 long isoform as widely upregulated in non-splicesome mutated acute myeloid leukemia and as altered by hypomethylating agent therapy.

作者：Eric Vick, Sean Walulik, Avery Sampson, Aishlin Hassan, Mark Wunderlich, Andrew Volk, Daniel T. Starczynowski · 发表于：Journal of Clinical Oncology · 年份：2025 · DOI：10.1200/jco.2025.43.16_suppl.6524 · 研究领域：Acute Myeloid Leukemia Research、Histone Deacetylase Inhibitors Research、Epigenetics and DNA Methylation

6524 Background: IRAK4, a kinase effector of MyD88 signaling downstream of Toll-Like Receptor and IL-1 receptor pathways, has recently been shown to function independently of MyD88 in Myelodysplastic Syndrome (MDS) and AML leukemic cells. Our previous research demonstrated that AML leukemic stem and progenitor cells (LSPC) rely on signaling through IRAK4. Notably, AML LSPCs express a hypermorphic long splice isoform of IRAK4 (IRAK4-L) resulting from the inclusion of exon 4. IRAK4 inhibitors, currently in clinical trials for the treatment of MDS and AML, show improved efficacy in spliceosome mutants, which preferentially express IRAK4-L. However, in patients without known spliceosome mutations, the extent of IRAK4-L expression remains unclear. Additionally, the impact of IRAK4-L levels in Venetoclax and Azacitidine treatment is unknown in refractory or unfit AML. Methods: Umbilical cord vein blood stem cells expressing MLL-AF9 and NRAS G12D (CD34+MA9.NRAS) were maintained in vitro using supplemented media. Venetoclax and Azacitidine doses were incrementally increased in combination until cells tolerated co-treatment with up to 1 µM of each compound with minimal cell death. Patient-derived xenograft (PDX) samples were obtained from the Cincinnati Children’s Biobank and included AML samples from diverse genetic backgrounds, relapsed/refractory cases, and pediatric populations (ages 1-20). Cell lysates were normalized to total protein and analyzed using a chemiluminescent capilla...