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. 2016 Jun 3;6(6):e431.
doi: 10.1038/bcj.2016.36.

Transcriptome Analysis of G Protein-Coupled Receptors in Distinct Genetic Subgroups of Acute Myeloid Leukemia: Identification of Potential Disease-Specific Targets

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Free PMC article

Transcriptome Analysis of G Protein-Coupled Receptors in Distinct Genetic Subgroups of Acute Myeloid Leukemia: Identification of Potential Disease-Specific Targets

A Maiga et al. Blood Cancer J. .
Free PMC article

Abstract

Acute myeloid leukemia (AML) is associated with poor clinical outcome and the development of more effective therapies is urgently needed. G protein-coupled receptors (GPCRs) represent attractive therapeutic targets, accounting for approximately 30% of all targets of marketed drugs. Using next-generation sequencing, we studied the expression of 772 GPCRs in 148 genetically diverse AML specimens, normal blood and bone marrow cell populations as well as cord blood-derived CD34-positive cells. Among these receptors, 30 are overexpressed and 19 are downregulated in AML samples compared with normal CD34-positive cells. Upregulated GPCRs are enriched in chemokine (CCR1, CXCR4, CCR2, CX3CR1, CCR7 and CCRL2), adhesion (CD97, EMR1, EMR2 and GPR114) and purine (including P2RY2 and P2RY13) receptor subfamilies. The downregulated receptors include adhesion GPCRs, such as LPHN1, GPR125, GPR56, CELSR3 and GPR126, protease-activated receptors (F2R and F2RL1) and the Frizzled family receptors SMO and FZD6. Interestingly, specific deregulation was observed in genetically distinct subgroups of AML, thereby identifying different potential therapeutic targets in these frequent AML subgroups.

Figures

Figure 1
Figure 1
Identification of overexpressed GPCRs in AML. RNA-Seq was used to determine expression levels of 772 GPCRs in 148 AML samples of the Leucegene cohort and 12 samples of normal cord blood-derived CD34+ CD45RA cells. The 50 GPCRs with the highest median expression levels in AML samples are presented in the heatmap. The 15 GPCRs that have a higher expression level as defined in Supplementary Figure 1A are in bold. NK, normal karyotype; Int.abn., Intermediate abnormal karyotype; MLL+, AML with MLL translocations; EVI1+, AML with EVI1 rearrangements; Complex, AML with three or more unrelated clonal chromosomal abnormalities. Boxes in green, blue or gray represent one sample with NUP98-NSD1 fusion, 17p deletion or an insufficient number of metaphases respectively. RNA-Seq data were transformed to lRPKM (log2(RPKM+1)).
Figure 2
Figure 2
Relation between GPCR expression in AML and in normal cord blood-derived CD34+ cells. The median gene expression level of 772 GPCRs in AML cells (y axis) is represented against their expression in normal cord blood-derived CD34+ cells (x axis). The 30 upregulated GPCRs in AML (blue dots) have a difference in median expression level between AML and normal CD34+ cells greater than 1. The 19 downregulated GPCRs in AML (green dots) have a difference in median expression less than −1. GPCRs represented in black dots are not differentially expressed between AML and normal CD34+ cells. RNA-Seq data were transformed to lRPKM (log2(RPKM+1)).
Figure 3
Figure 3
GPCR subfamily distribution of upregulated and downregulated GPCRs in AML. The left panel shows the proportion of genes upregulated or downregulated in AML and all GPCRs into different subfamilies of GPCRs (adhesion, amine, chemokine and so on). The P-values are indicated for significant families by Fisher's exact tests. The right panel shows individual GPCRs of enriched groups. Values indicated in second and third columns correspond to the receptor mean expression level in AML and CD34+ cells. All represented GPCRs have mean expression levels in AML significantly different from their mean in normal CD34+ cells, P-values<0.005. The Fisher's exact test was performed between the upregulated or downregulated group and remaining GPCRs, i.e., all GPCRs excluding differentially expressed genes.
Figure 4
Figure 4
GPCR expression level analysis in AML of different genetic subgroups. Expression of deregulated GPCRs in AML samples with (a) t(8;21), inv(16) and MLL translocations and (b) normal karyotype with FLT3-ITD or NPM1 mutations. Differentially expressed GPCRs are defined as having a difference in mean expression higher or equal to 1.5 lRPKM between samples with (+) and without (−) the genetic abnormality and a significant Student's t test (P<0.05). Only GPCRs that were validated in the TCGA dataset are shown. Data are expressed as individual sample expression value and means ±1 s.e.m. for all samples. Mean expression of GPCRs in normal CD34+ cells is illustrated with a green dashed line. (c) List of GPCRs with a significant difference in mean expression level in AML samples of representative genetic subgroups in Leucegene and TCGA cohorts. RNA-Seq data were transformed to lRPKM (log2(RPKM+1)).
Figure 5
Figure 5
Expression levels of GPCRs overexpressed in specific AML genetic subgroups in AML, normal blood and bone marrow cells. Expression levels of GPCRs previously identified as overexpressed in specific genetic subgroups of AML are compared with their expression in normal blood and bone marrow cell populations. Represented GPCRs, i.e., ADRA2C and GPR153 in AML with t(8;21), GPR126 in AML with MLL translocations, CYSLTR2 in normal karyotype AML with NPM1 or FLT3-ITD mutations, and RXFP1 and CXCR7/ACKR3 in AML with inv(16), show a significant difference in mean expression between the specific AML genetic subgroup and each normal cell population identified (Student's t test (P<0.05)). AML samples are represented by red dots and normal cell samples by green, blue or gray dots. Data are expressed as individual sample expression value and means for all samples. Normal blood and bone marrow cell populations were prepared as described in the Materials and methods section. RNA-Seq data were transformed to lRPKM (log2(RPKM+1)). NK, normal karyotype; WBC, white blood cells; nBM, normal bone marrow.

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References

    1. Wisler JW, Xiao K, Thomsen AR, Lefkowitz RJ. Recent developments in biased agonism. Curr Opin Cell Biol 2014; 27: 18–24. - PMC - PubMed
    1. Bouvier M. Unraveling the structural basis of GPCR activation and inactivation. Nat Struct Mol Biol 2013; 20: 539–541. - PubMed
    1. O'Hayre M, Degese MS, Gutkind JS. Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr Opin Cell Biol 2014; 27: 126–135. - PMC - PubMed
    1. Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer 2007; 7: 79–94. - PubMed
    1. Even-Ram S, Uziely B, Cohen P, Grisaru-Granovsky S, Maoz M, Ginzburg Y et al. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med 1998; 4: 909–914. - PubMed

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