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

Abstract

Key Points• GPR84 simultaneously augments b-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.b-catenin is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). Targeted inhibition of b-catenin signaling has been hampered by the lack of pathway components amenable to pharmacologic manipulation. Here we identified a novel b-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 b-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 b-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 b-catenin signaling in LSCs, and suggest that targeting the oncogenic GPR84/b-catenin signaling axis may represent a novel therapeutic strategy for AML. (Blood. 2014;124(22):3284-3294) IntroductionThe ability for self-renewal, migration/invasion, and drug resistance are fundamental properties of malignant stem cells that drive both disease progression and relapse. Identification of pathways and their molecular components essential for the regulation of abnormally acquired stem cell-like properties is a prerequisite for understanding the underlying mechanisms of oncogenesis and designing effective anticancer therapeutic strategies. We and others have previously shown that mixed-lineage leukemia (MLL) fusion proteins can aberrantly activate Wnt/b-catenin signaling in hematopoietic stem cells (HSCs) or more differentiated granulocyte-macrophage progenitors (GMPs) for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia subtype M5 (AML-M5) 1,2 ; however, the mechanisms involved remain obscure. It has also been noted that activation of b-catenin is observed in tumors without clear mutations in major components of this pathway or an increase in Wnt signaling.3 This suggests that other developmental signaling pathways may be capable of inducing activation or downstream signaling of b-catenin.G protein-coupled receptors (GPCRs), the largest family of cell-surface molecules with key roles in transmitting signals to downstream effectors, ...

The biomarkers of leukemia stem cells in acute myeloid leukemia

“…The Wnt/β-catenin was active in human LSCs and in HSCs while β-catenin was unnecessary for the selfrenew of adult HSCs (43)(44)(45). Meanwhile, pharmacological inhibition of β-catenin impaired LSC function and significantly reduced the growth of human MLL leukemic cells (46,47). Therefore, all these transcription factors might be considered to be potential targets for selectively ablating LSCs.…”

miR‐200c suppresses stemness and increases cellular sensitivity to trastuzumab in HER2+ breast cancer

“…Like normal tissues, tumour tissues are composed of a variety of heterogeneous tumour cells and originate from corresponding stem cells. CSCs have been isolated from a variety of tumours, such as leukaemia, lung cancer and breast cancer . There are two recognized methods of separating BCSCs from breast cancer patients and cell lines: one is surface phenotypic marker screening, and the other is Hoechst 33 342 dye exclusion.…”

G protein‐coupled receptor 84 controls osteoclastogenesis through inhibition of NF‐κB and MAPK signaling pathways

“…In addition, a previous study reported that GPR84 is a proinflammatory receptor and may be a target to treat chronic, low‐grade inflammation related‐disorders (Suzuki et al, ). GPR84 is also known to modulate leukemogenesis and to possess a novel therapeutic potential against acute myeloid leukemia (Dietrich et al, ). Although GPR84 has been reported to mainly regulate immune responses in many cell types, the role of GPR84 in osteoclast differentiation has yet to be determined.…”