GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis

• Published in: Blood 2014-11, Vol.124 (22), p.3284-3294
• Main Authors: Dietrich, Philipp A., Yang, Chen, Leung, Halina H.L., Lynch, Jennifer R., Gonzales, Estrella, Liu, Bing, Haber, Michelle, Norris, Murray D., Wang, Jianlong, Wang, Jenny Yingzi
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cells, Cultured; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Mice, Inbred C57BL; Microarray Analysis; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Receptors, Cell Surface - physiology; Receptors, G-Protein-Coupled; Signal Transduction - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-10-532523

β-catenin is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). Targeted inhibition of β-catenin signaling has been hampered by the lack of pathway components amenable to pharmacologic manipulation. Here we identified a novel β-catenin regulator, GPR84, a member of the G protein-coupled receptor family that represents a highly tractable class of drug targets. High GPR84 expression levels were confirmed in human and mouse AML LSCs compared with hematopoietic stem cells (HSCs). Suppression of GPR84 significantly inhibited cell growth by inducing G1-phase cell-cycle arrest in pre-LSCs, reduced LSC frequency, and impaired reconstitution of stem cell–derived mixed-lineage leukemia (MLL) AML, which represents an aggressive and drug-resistant subtype of AML. The GPR84-deficient phenotype in established AML could be rescued by expression of constitutively active β-catenin. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a-transduced stem cells. Microarray analysis demonstrated that GPR84 significantly upregulated a small set of MLL-fusion targets and β-catenin coeffectors, and downregulated a hematopoietic cell-cycle inhibitor. Altogether, our data reveal a previously unrecognized role of GPR84 in maintaining fully developed AML by sustaining aberrant β-catenin signaling in LSCs, and suggest that targeting the oncogenic GPR84/β-catenin signaling axis may represent a novel therapeutic strategy for AML. •GPR84 simultaneously augments β-catenin signaling and an oncogenic transcription program essential for establishment of MLL.•Our study demonstrates a strong dependence of hematopoietic stem cell–derived MLL leukemic cells on GPR84 for disease maintenance in vivo.