Therapeutic targeting of MLL degradation pathways in MLL‐rearranged leukemia

作者：Kaiwei Liang, Andrew Volk, Jeffrey S. Haug, Stacy A. Marshall, Ashley R. Woodfin, Elizabeth T. Bartom, Joshua M. Gilmore, Laurence Florens, Michael P. Washburn, Kelly D. Sullivan, Joaquı́n M. Espinosa, Joseph Cannova, Jiwang Zhang, Edwin R. Smith, John D. Crispino, Ali Shilatifard · 发表于：The FASEB Journal · 年份：2017 · DOI：10.1096/fasebj.31.1_supplement.611.1 · 被引用次数：9 · 研究领域：Acute Myeloid Leukemia Research、Advanced biosensing and bioanalysis techniques、Protein Degradation and Inhibitors

Chromosomal translocations of the mixed‐lineage leukemia ( MLL ) gene with various partner genes result in aggressive MLL leukemia with dismal outcomes. Despite relatively equal contributions of the rearranged allele and the remaining wild‐type allele at the mRNA level, the MLL chimeric protein is much more stable than the wild‐type MLL protein. Here, we used Multidimensional Protein Identification Technology (MudPIT) and established a pooled genome‐wide shRNA library screen to identify the factors and pathways involved in regulating the stability of the wild‐type MLL protein. Targeting wild‐type MLL degradation, through blocking of these pathways and factors, preferentially impedes MLL leukemia cell proliferation and downregulates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the Super Elongation Complex (SEC), as revealed by RNA sequencing and Chromatin Immunoprecipitation Sequencing (ChIP‐Seq). Stabilizing wild‐type MLL protein by inhibition of these pathways displaces the MLL chimera from some of its target genes and therefore relieves the cellular oncogenic addiction to MLL chimeras. Furthermore, pharmacologically inhibition of these pathways with small molecules substantially delays progression and improves survival of murine MLL‐AF9 leukemia in vivo. Therefore, disrupting the balance between wild‐type MLL and MLL chimeras by stabilization of MLL provides us with a paradigm in the development of therapies for aggressive MLL leukemia ...