Immunoproteasome function maintains oncogenic gene expression in KMT2a-rearranged leukemia [RNA-seq I]

Pharmacologic targeting of epigenetic protein complexes has shown significant in vitro responses in AML. Early clinical trials in MLL-rearranged leukemia indicate rather transient responses and development of resistance. In an effort to define functional dependencies of MLL-fusions in acute myeloid leukemia, we identify the catalytic immunoproteasome subunit PSMB8 as an oncogene-specific vulnerability. Genetic and pharmacologic inactivation of PSMB8 results in impaired proliferation of murine and human leukemic cells while normal hematopoietic cells remain unaffected. Disruption of immunoproteasome function results in cellular enrichment of transcription factor BASP1, and consecutive repression of MLL-target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, eradicates leukemia in primary human xenografts and shows preserved activity against Menin-inhibitor resistance mutations. This identifies and validates a cell-intrinsic mechanism whereby selectivity of proteostasis results in altered transcription factor abundance and repression of oncogene-specific transcriptional networks. Therapeutic targeting of PSMB8-dependent transcription in combination with Menin-inhibition could thus eradicate AML harboring MLL-rearrangements. Comparative gene expression profiling analysis of RNA-seq data for MOLM-13 cells treated with 100nM PR-957 (ONX-0914) or diluent treated controls for 72hours.

表观遗传蛋白复合物的药理学靶向策略已在急性髓系白血病（Acute Myeloid Leukemia, AML）中展现出显著的体外抗肿瘤应答。针对MLL重排白血病（MLL-rearranged leukemia）的早期临床试验则显示，此类治疗的应答相当短暂且易产生耐药性。为明确急性髓系白血病中MLL融合基因的功能依赖特性，本研究鉴定出免疫蛋白酶体催化亚基PSMB8为癌基因特异性的易感靶点。对PSMB8进行遗传与药理学失活，可抑制小鼠及人类白血病细胞的增殖，而正常造血细胞未受影响。免疫蛋白酶体功能的破坏会导致转录因子BASP1在细胞内富集，并进而抑制MLL靶基因的表达。靶向PSMB8的药理学治疗可增强Menin抑制剂（Menin-inhibitors）的疗效，能够在原代人源异种移植瘤模型中根除白血病细胞，且对Menin抑制剂耐药突变体仍保有治疗活性。上述结果确认并验证了一种细胞内在机制：蛋白质稳态（proteostasis）的选择性调控可改变转录因子的丰度，进而抑制癌基因特异性的转录网络。因此，联合靶向PSMB8依赖的转录过程与Menin抑制策略，有望根除携带MLL重排的急性髓系白血病。本数据集对应经100nM PR-957（ONX-0914）或溶剂对照处理72小时的MOLM-13细胞系的RNA测序（RNA-seq）数据的比较基因表达谱分析结果。