Transcriptome analysis of G protein-coupled receptors in distinct genetic subgroups of acute myeloid leukemia: identification of potential disease-specific targets

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. Total healthy bone marrow was sorted to isolate distinct cell populations. RNA-Seq analysis was performed on sorted cells to determine gene expression profile of healthy bona marrow subpopulations.

急性髓系白血病（Acute myeloid leukemia, AML）临床预后不佳，亟需开发更为高效的治疗手段。G蛋白偶联受体（G protein-coupled receptors, GPCRs）是极具吸引力的治疗靶点，占已上市药物靶点总数的约30%。本研究借助下一代测序技术，对148份遗传异质性AML标本、正常血液与骨髓细胞群以及脐带血来源的CD34阳性细胞中的772种GPCR的表达情况进行了分析。相较于正常CD34阳性细胞，AML样本中有30种GPCR过表达，19种GPCR表达下调。过表达的GPCR富集于趋化因子受体（CCR1、CXCR4、CCR2、CX3CR1、CCR7及CCRL2）、黏附受体（CD97、EMR1、EMR2及GPR114）以及嘌呤受体（包括P2RY2与P2RY13）亚家族。下调的受体涵盖黏附类GPCR，如LPHN1、GPR125、GPR56、CELSR3及GPR126、蛋白酶激活受体（F2R与F2RL1）以及Frizzled家族受体SMO与FZD6。值得注意的是，在遗传特征各异的AML亚组中观测到了特异性的表达失调现象，由此为这类高发的AML亚组甄别出了不同的潜在治疗靶点。研究人员通过分选完整健康骨髓以分离不同细胞群，并对分选后的细胞开展RNA测序（RNA-Seq）分析，以明确健康骨髓亚群的基因表达谱。