PO.TB10.05 · 肿瘤生物学

前列腺素E2信号促进B细胞急性淋巴细胞白血病的不良生存结局

Prostaglandin E 2 signaling promotes adverse survival outcome in B-cell acute lymphoblastic leukemia

编号 2088 展板 18 时间 4/20 09:00–12:00 区域 Section 26 主讲 Michael Cohen, PhD

分会场 Aging and Host Determinants of Tumor Progression: The Macroenvironmental Axis

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作者与单位 Authors & Affiliations

Michael Cohen¹, Nayaonika Vasishtha¹, Byourak Shabane¹, Jia Tan¹, Tyler Kuk¹, Neha Chandra¹, In Sook Ahn¹, Xia Yang¹, Etan Orgel², Steven D. Mittelman¹

¹UCLA - University of California Los Angeles, Los Angeles, CA,²Children's Hospital Los Angeles, Los Angeles, CA

摘要 Abstract

中文摘要

肥胖增加急性淋巴细胞白血病（ALL）的风险并恶化其治疗结局。为探索脂肪组织如何促成这些效应，我们此前在肥胖小鼠中进行了单细胞RNA测序，以比较脂肪组织来源ALL与骨髓来源ALL的基因表达。我们鉴定出577个差异表达基因（DEGs），log2倍数阈值为±0.25，Bonferroni校正p值<0.05。使用ALL与人脂肪外植体的离体共培养，我们证实脂肪组织通过分泌前列腺素E2（PGE2）在ALL细胞中上调一个顶级DEG——TNFSF11。此外，我们观察到PGE2在体外赋予对长春新碱和柔红霉素化疗的中度耐药性。在本研究中，我们探讨了脂肪组织PGE2是否可能促成ALL的不良治疗结局。我们在前50个DEGs中鉴定出另外六个可能由PGE2-cAMP信号诱导的基因，并证实这些基因在BV173和RS4;11 ALL细胞系中被200 ng/mL PGE2在体外上调（表）（N=6）。为研究这些基因与ALL生存的相关性，我们使用NCI GDC数据门户分析了TARGET-ALL P2临床试验的数据。TARGET-ALL P2纳入了在儿童肿瘤协作组（Children's Oncology Group）方案下治疗的儿童和青年B前体ALL患者，富集了诊断后4年内复发的患者。466名受试者的诊断标本可获得生存和RNAseq表达数据。这六个基因以及TNFSF11的表达与显著更差的生存相关，风险比范围为1.7至3.7（表）。总体而言，我们的数据表明，脂肪组织PGE2可上调与ALL患者更差预后相关的基因。需要进一步研究以检验脂肪组织PGE2是否是肥胖患者ALL结局更差的促成因素。基因名称符号 log2 FC 脂肪 vs. 骨髓（scRNAseq） PGE2作用下倍数变化（qPCR）BV173, RS4;11 p值 BV173, RS4;11 风险比 Log-rank p值 TNF超家族成员11 TNFSF11 2.195 5.50, 7.34 0.0020, 0.0365 1.731 0.0043 Fos原癌基因，AP-1转录因子亚基 FOS 1.809 2.18, 4.31 0.029, 0.0004 2.025 0.0004 Fos样2，AP-1转录因子亚基 FOSL2 1.561 4.8, 7.67 0.0015, 0.0008 2.289 <0.0001 JunB原癌基因，AP-1转录因子亚基 JUNB 2.730 1.70, 1.24 0.034, 0.023 3.523 <0.0001 JunD原癌基因，AP-1转录因子亚基 JUND 1.616 1.51, 1.87 0.076（n.s.）, 0.0017 3.748 <0.0001 核受体亚家族4 A组成员1 NR4A1 2.184 3.07, 6.63 0.016, 0.0008 2.483 <0.0001 核受体亚家族4 A组成员2 NR4A2 1.871 2.41, 8.10 0.0005, 0.0022 3.431 <0.0001

查看英文原文 English abstract

Obesity increases risk and worsens treatment outcome of acute lymphoblastic leukemia (ALL). To explore how adipose tissue may contribute to these effects, we previously performed single cell RNA sequencing in obese mice to compare gene expression in ALL from adipose tissue to ALL from marrow. We identified 577 differentially expressed genes (DEGs) with a log 2 -fold threshold of ±0.25 and Bonferroni corrected p-values <0.05. Using ex-vivo coculture of ALL and human adipose explants, we confirmed that adipose tissue upregulates a top DEG, TNFSF11 , in ALL cells via secretion of prostaglandin E2 (PGE 2 ). Additionally, we observed that PGE 2 conferred modest resistance in vitro to vincristine and daunorubicin chemotherapies. In the present study, we explored whether adipose tissue PGE 2 might contribute to poor ALL treatment outcome. We identified six additional genes in the top 50 DEGs that may be induced by PGE 2 -cAMP signaling and confirmed that these genes were upregulated in vitro by 200 ng/mL PGE 2 in BV173 and RS4;11 ALL cell lines (Table)(N=6). To investigate the relevance of these genes to ALL survival, we analyzed data from the TARGET-ALL P2 clinical trial using the NCI GDC Data Portal. TARGET-ALL P2 included pediatric and young adult B-precursor ALL patients treated on Children's Oncology Group protocols, enriched for patients who experienced relapse within 4 years of diagnosis. Survival and RNAseq expression on diagnostic specimens were available for 466 subjects. Expression of these six genes, as well as TNFSF11 , was associated with significantly worse survival, with hazard ratios ranging from 1.7 to 3.7 (Table). Overall, our data shows that adipose tissue PGE 2 can upregulate genes that are associated with a worse prognosis in ALL patients. Further work is needed to test whether adipose tissue PGE 2 is a contributing factor for worse ALL outcomes in obese patients. Gene name Symbol Log 2 FC adipose vs. marrow (scRNAseq) Fold change with PGE 2 (qPCR) BV173, RS4;11 p-value BV173, RS4;11 Hazard ratio Log-rank p-value TNF superfamily member 11 TNFSF11 2.195 5.50, 7.34 0.0020, 0.0365 1.731 0.0043 Fos proto-oncogene, AP-1 transcription factor subunit FOS 1.809 2.18, 4.31 0.029, 0.0004 2.025 0.0004 Fos like 2, AP-1 transcription factor subunit FOSL2 1.561 4.8, 7.67 0.0015, 0.0008 2.289 <0.0001 JunB proto-oncogene, AP-1 transcription factor subunit JUNB 2.730 1.70, 1.24 0.034, 0.023 3.523 <0.0001 JunD proto-oncogene, AP-1 transcription factor subunit JUND 1.616 1.51, 1.87 0.076 (n.s.), 0.0017 3.748 <0.0001 Nuclear receptor subfamily 4 group A member 1 NR4A1 2.184 3.07, 6.63 0.016, 0.0008 2.483 <0.0001 Nuclear receptor subfamily 4 group A member 2 NR4A2 1.871 2.41, 8.10 0.0005, 0.0022 3.431 <0.0001

利益披露 Disclosure

M. Cohen, None.. N. Vasishtha, None.. B. Shabane, None.. J. Tan, None.. T. Kuk, None.. N. Chandra, None.. I. Ahn, None.. X. Yang, None.. E. Orgel, None.. S. D. Mittelman, None.

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