Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The important role of GPR84 in MLL leukemogenesis

ABSTRACT: Beta-catenin signaling is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), yet the upstream regulators that can augment this pathway are unknown. Through genome-wide gene expression analysis and functional studies, we identified an important role for GPR84 in MLL AML. Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of MLL AML. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a transduced hematopoietic stem cells (HSCs). Our microarray analysis demonstrated that GPR84 overexpression significantly up-regulated a small set of MLL-fusion targets and beta-catenin co-effectors, and down-regulated a hematopoietic cell cycle inhibitor. These data thus reveal a previously unrecognized role of GPR84 in the maintenance of fully developed AML by sustaining aberrant beta-catenin signaling in LSCs. HSC-derived Hoxa9/Meis1a pre-LSCs were transduced with GPR84 cDNA or empty vector, and replated in methylcellulose supplemented with cytokines. Each group contains triplicate samples.

ORGANISM(S): Mus musculus

SUBMITTER: Jenny Wang 

PROVIDER: E-MTAB-1932 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Dietrich Philipp A PA   Yang Chen C   Leung Halina H L HH   Lynch Jennifer R JR   Gonzales Estrella E   Liu Bing B   Haber Michelle M   Norris Murray D MD   Wang Jianlong J   Wang Jenny Yingzi JY  

Blood 20141007 22

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  ...[more]

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