CN117305465B - 一种用于预测多种儿童白血病预后的生物标志物、评分模型及其应用 - Google Patents
一种用于预测多种儿童白血病预后的生物标志物、评分模型及其应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域，特别是涉及一种用于预测多种儿童白血病预后的生物标志物、评分模型及其应用。本发明提供了一种用于预测多种儿童白血病预后的生物标志物，所述生物标志物包括CD99基因、TMSB4X基因、SOX4基因、KLF6基因、PLIN2基因、CD69基因、CORO1A基因、CD47基因和MARCKSL1基因。本发明利用9个基因对儿童白血病患者的预后情况进行预测，能够准确获得儿童白血病患者预后情况。
Description
技术领域
本发明涉及生物医药领域，特别是涉及一种用于预测多种儿童白血病预后的生物标志物、评分模型及其应用。
背景技术
白血病是一种血液系统恶性肿瘤，其起源于失去了正常自我更新、分化或凋亡能力的造血干祖细胞。白血病的临床表现主要包括由于正常造血细胞生成减少，导致的感染、发热、出血和贫血；也可由于白血病细胞浸润导致肝、脾和淋巴结肿大及其他器官病变。儿童白血病是儿童恶性肿瘤中最常见的类型，约占儿童肿瘤患者的20-30％，其中急性淋巴细胞白血病(Acute lymphoblastic leukemia，ALL)最为常见，还包括急性髓系白血病(Acutemyeloid leukemia，AML)和混合表型急性白血病(mixedphenotype acute leukemia，MPAL)等类型。虽然儿童急性白血病，尤其是儿童急性淋巴细胞白血病的临床治疗效果在过去几十年中取得了显著改善，但仍有一部分患者会发生复发并最终导致死亡等不良结局。
在复发难治性白血病中，存在一群具有干性特征的细胞群，称为白血病干细胞(leukemia stem cells，LSC)，它们保持相对静止状态并能够在需要时补充原始细胞群。大量研究结果表明LSC可能在复发难治性白血病中发挥重要作用。此外，临床研究还发现LSC与微小残留病增加有关，这些患者的复发率较高，生存率较低。但基于机体内免疫反应的发生涉及多种免疫细胞的参与，而且目前对于预后的评估并不完整。因此，寻找能够准确预测多种儿童白血病预后情况的相关因素，并对不同预后的患者采取针对性的治疗具有重要意义。
发明内容
本发明的目的是提供一种用于预测多种儿童白血病预后的生物标志物、评分模型及其应用，以解决上述现有技术存在的问题。本发明利用9个基因对儿童白血病患者的预后情况进行预测，能够准确获得儿童白血病患者预后情况。
为实现上述目的，本发明提供了如下方案：
本发明提供了一种用于预测多种儿童白血病预后的生物标志物，所述生物标志物包括CD99基因、TMSB4X基因、SOX4基因、KLF6基因、PLIN2基因、CD69基因、CORO1A基因、CD47基因和MARCKSL1基因。
优选的，所述白血病包括急性髓系白血病、急性淋巴细胞白血病和混合表型急性白血病。
本发明提供了检测生物标志物的制剂在制备预测多种儿童白血病预后的产品中的应用，所述生物标志物包括CD99基因、TMSB4X基因、SOX4基因、KLF6基因、PLIN2基因、CD69基因、CORO1A基因、CD47基因和MARCKSL1基因。
优选的，所述白血病包括急性髓系白血病、急性淋巴细胞白血病和混合表型急性白血病。
本发明提供了生物标志物在构建儿童白血病预后风险评分模型中的应用，所述生物标志物包括CD99基因、TMSB4X基因、SOX4基因、KLF6基因、PLIN2基因、CD69基因、CORO1A基因、CD47基因和MARCKSL1基因。
优选的，所述白血病包括急性髓系白血病、急性淋巴细胞白血病和混合表型急性白血病。
本发明提供了一种儿童白血病预后风险评分模型，所述模型以生物标志物表达水平作为输入变量，构建儿童白血病预后风险评分模型；所述的生物标志物包括CD99基因、TMSB4X基因、SOX4基因、KLF6基因、PLIN2基因、CD69基因、CORO1A基因、CD47基因和MARCKSL1基因；所述的模型使用以下方程计算风险得分：
所述儿童白血病预后风险评分模型包括AML模型、T-ALL模型和MPAL模型；
所述AML模型使用以下方程计算风险得分：
风险得分＝0.105225*CD69基因表达水平-0.0338431*CD99基因表达水平-0.0449341*TMSB4X基因表达水平-0.2092702*PLIN2基因表达水平-0.0675673*MARCKSL1基因表达水平+0.0002883*SOX4基因表达水平-0.0138693*KLF6基因表达水平-0.1168628*CD47基因表达水平+0.0287487*CORO1A基因表达水平；
所述T-ALL模型使用以下方程计算风险得分：
风险得分＝(-0.06924)*CD69基因表达水平+0.14446*CD99基因表达水平-0.31483*TMSB4X基因表达水平+0.21472*PLIN2基因表达水平+0.3215*MARCKSL1基因表达水平-0.25352*SOX4基因表达水平-0.03651*KLF6基因表达水平+0.3148*CD47基因表达水平+0.39645*CORO1A基因表达水平；
所述MPAL模型使用以下方程计算风险得分：
风险得分＝(-0.05335)*CD69基因表达水平-0.52334*CD99基因表达水平-0.24722*TMSB4X基因表达水平-0.54121*PLIN2基因表达水平-0.18649*MARCKSL1基因表达水平+0.24516*SOX4基因表达水平+0.77431*KLF6基因表达水平+0.15399*CD47基因表达水平+0.08337*CORO1A基因表达水平。
本发明提供了上述的儿童白血病预后风险评分模型在构建儿童白血病预后系统或装置中的应用，根据儿童白血病预后风险评分模型的评分结果对儿童白血病患者进行分组，预测儿童白血病患者预后。
优选的，根据所述评分结果预测儿童白血病患者预后的标准为：当评分结果为AML≥-0.01389317、T-ALL≥0.0190043且MPAL≥0.04315561的患者作为高危组，当评分结果为AML＜-0.01389317、T-ALL<0.0190043且MPAL<0.04315561的患者时作为低危组；所述高危组预后效果不佳。
优选的，所述儿童白血病包括急性髓系白血病、急性淋巴细胞白血病和混合表型急性白血病。
本发明公开了以下技术效果：
本发明利用单细胞转录组技术来解析在多种儿童白血病患者的白血病干细胞，发现9种共同影响患者预后的关键基因。将该9种关键基因作为用于预测多种儿童白血病预后的生物标志物，并构建与之相关的预测多种儿童白血病预后的评分模型，能够准确、有效预测儿童白血病患者的预后情况，能够为患者的治疗提供方向，也便于在各个医院中推广使用。
本发明还提供了一种儿童白血病预后风险评分模型，该儿童白血病预后风险评分模型能够利用少量基因的表达量特征，来推断多种儿童白血病患者的预后分层。在本发明具体实施例中，该儿童白血病预后风险评分模型在AML、ALL和MPAL多种儿童白血病亚型中均能有效地预测患者的预后分层，能够用简单的指标预测多种不同白血病的预后，使用方便简洁。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为健康儿童的骨髓细胞分群的UMAP图，其中横坐标为维度1，纵坐标为维度2；
图2为不同样本中细胞比例组成的聚类热图，其中，HD860代表860号健康供者，HD032代表032号健康供者，HD490代表490号健康供者，HD170代表170号健康供者，B-ALL011代表011号B-ALL(急性B淋巴细胞性白血病)患者，B-ALL734代表734号B-ALL患者，B-ALL887代表887号B-ALL患者，B-ALL328代表328号B-ALL患者，MPAL294代表294号MPAL患者，B-ALL069代表069号B-ALL患者，B-ALL265代表265号B-ALL患者，MPAL019代表019号MPAL患者，B-ALL590代表590号B-ALL患者，B-ALL998代表998号B-ALL患者，T-ALL305代表305号T-ALL(T细胞急性淋巴细胞白血病)患者，T-ALL788代表788号T-ALL患者，T-ALL723代表723号T-ALL患者，MPAL561代表561号MPAL患者，T-ALL593代表593号T-ALL患者，T-ALL956代表956号T-ALL患者，T-ALL856代表856号T-ALL患者，AML944代表944号AML患者，AML661代表661号AML患者，AML770代表770号AML患者，AML803代表803号AML患者，MPAL790代表790号MPAL患者，MPAL628代表628号MPAL患者；
图3为HSC/MPP样亚群中各白血病亚型特异和共有的差异表达基因聚类热图和对应的富集信号通路；
图4为不同患者的预后情况分析图，其中，HSC/MPP Signature Score代表HSC/MPP基因集打分，Overal survival代表总体生存率，Target-AML-Traing set代表来源于Target队列的急性髓系白血病模型，Target-AML-Validation set代表来源于Target队列的急性髓系白血病验证集，Target-MPAL-T/myeloid代表来源于Target队列的T/髓系型混合表型急性白血病(T/M亚型的MPAL)数据集，Target-TALL代表来源于Target队列的急性T淋巴细胞白血病数据集。
具体实施方式
现详细说明本发明的多种示例性实施方式，该详细说明不应认为是对本发明的限制，而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式，并非用于限制本发明。另外，对于本发明中的数值范围，应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值，以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明，否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料，但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入，用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时，以本说明书的内容为准。
在不背离本发明的范围或精神的情况下，可对本发明说明书的具体实施方式做多种改进和变化，这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见得的。本发明说明书和实施例仅是示例性的。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等，均为开放性的用语，即意指包含但不限于。
实施例1构建健康儿童和儿童白血病患者的单细胞转录组图谱
首先，取健康儿童的骨髓单个核细胞和经流式分选的CD34+造血干祖细胞，以及儿童AML、B-ALL、T-ALL和MPAL患者的骨髓单个核细胞进行5’端10×单细胞转录组测序；
利用健康儿童的单细胞测序数据构建健康儿童骨髓造血干祖细胞的分化图谱。如图1所示，健康儿童一共获得了98906个质控合格的细胞，根据细胞的转录组特征，无监督聚类可以将细胞分为23个亚群，根据已报道的谱系特征相关基因，细胞群主要分为四大类：HSC/MPP亚群、红系细胞亚群、髓系细胞亚群和淋系细胞亚群。
将来源于23个儿童白血病患者的14259个质控合格的单细胞转录组数据映射到健康儿童细胞构建的图谱上。结果显示，B-ALL和T-ALL的白血病细胞主要分布在LMPP样亚群和CLP样亚群，AML细胞广泛分布于髓系细胞亚群的中性粒细胞样亚群和单核细胞样亚群中，MPAL细胞则同时拥有髓系细胞亚群和淋系细胞亚群的特征。
实施例2不同白血病亚型中共有的HSC/MPP样亚群特征
通过对比不同儿童白血病患者的细胞亚群比例组成，我们发现4/6的T-ALL患者、所有的AML患者和所有的T/M亚型的MPAL患者(MPAL790和MPAL28)均具有高丰度的HSC/MPP样亚群特征(图2)。
进一步探究了不同白血病亚型中HSC/MPP样亚群和其他亚群的差异基因(差异基因是指变化倍数超过2倍的基因)，结果如图3所示，发现了在三种白血病亚型中共有的146个上调基因和122个下调基因。共同上调的基因主要富集在氧化磷酸化、有氧呼吸和ATP代谢等信号通路中，而共同下调基因则主要富集在细胞质翻译和氧转运等方面，表明HSC/MPP样亚群中出现了明显的代谢重编程。
实施例3构建一组预测多种儿童白血病预后的基因集合
基于三种白血病类型中共有的上调基因，构建一个能够预测多种儿童白血病预后的HSC/MPP样亚群特征。根据平均的log2(FoldChange)>1和基因功能注释，从146个上调基因中筛选了9个基因组成了HSC/MPP样亚群基因特征用于预后分析，具体为：CD99基因、TMSB4X基因、SOX4基因、KLF6基因、PLIN2基因、CD69基因、CORO1A基因、CD47基因和MARCKSL1基因。
利用Cox比例风险模型计算各个基因的预后风险系数，最终得到患者预后危险评分模型：
AML模型的风险得分＝0.105225*CD69基因表达水平-0.0338431*CD99基因表达水平-0.0449341*TMSB4X基因表达水平-0.2092702*PLIN2基因表达水平-0.0675673*MARCKSL1基因表达水平+0.0002883*SOX4基因表达水平-0.0138693*KLF6基因表达水平-0.1168628*CD47基因表达水平+0.0287487*CORO1A基因表达水平。
T-ALL模型的风险得分＝(-0.06924)*CD69基因表达水平+0.14446*CD99基因表达水平-0.31483*TMSB4X基因表达水平+0.21472*PLIN2基因表达水平+0.3215*MARCKSL1基因表达水平-0.25352*SOX4基因表达水平-0.03651*KLF6基因表达水平+0.3148*CD47基因表达水平+0.39645*CORO1A基因表达水平。
MPAL模型的风险得分＝(-0.05335)*CD69基因表达水平-0.52334*CD99基因表达水平-0.24722*TMSB4X基因表达水平-0.54121*PLIN2基因表达水平-0.18649*MARCKSL1基因表达水平+0.24516*SOX4基因表达水平+0.77431*KLF6基因表达水平+0.15399*CD47基因表达水平+0.08337*CORO1A基因表达水平。
采用上述评分模型对1586例患者(AML患者1296例，T-ALL患者243例，T/M亚型的MPAL患者47例，)的预后进行评估。根据各队列的风险得分的中位数将患者分为低危组(风险得分AML＜(-0.01389317)、T-ALL<0.0190043且MPAL<0.04315561)和高危组(AML≥(-0.01389317)、T-ALL≥0.0190043且MPAL≥0.04315561)2组，如图4显示，AML队列通过治疗方法的不同分为训练集和验证集2个队列，在2个队列中均可明显观察到高危组的患者预后明显差于低危组患者(p值分别为小于0.0001和0.014，P值由对数秩检验计算)；在T-ALL中和T/M亚型的MPAL中使用1000次的重抽样来验证模型的稳定性，同样可以观察到高危组的患者预后明显差于低危组患者(p值分别为小于0.0028和0.031，P值由对数秩检验计算)。由此可见，采用本发明所述评分模型进行评分后，评分结果较高的患者预后效果较差。
综上可知，我们成功地利用了多种儿童白血病中共有的HSC/MPP样基因特征构建了一组预测多种儿童白血病预后的基因集合以及评分模型。
以上所述的实施例仅是对本发明的优选方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案做出的各种变形和改进，均应落入本发明权利要求书确定的保护范围内。
Claims (5)
1.检测生物标志物的制剂在制备预测多种儿童白血病预后的产品中的应用，其特征在于，所述生物标志物包括CD99基因、TMSB4X基因、SOX4基因、KLF6基因、PLIN2基因、CD69基因、CORO1A基因、CD47基因和MARCKSL1基因。
2.根据权利要求1所述的应用，其特征在于，所述白血病包括急性髓系白血病、急性淋巴细胞白血病和混合表型急性白血病。
3.儿童白血病预后风险评分模型在构建儿童白血病预后系统或装置中的应用，其特征在于，根据儿童白血病预后风险评分模型的评分结果对儿童白血病患者进行分组，预测儿童白血病患者预后；
所述儿童白血病预后风险评分模型以生物标志物表达水平作为输入变量，构建儿童白血病预后风险评分模型；所述的生物标志物包括CD99基因、TMSB4X基因、SOX4基因、KLF6基因、PLIN2基因、CD69基因、CORO1A基因、CD47基因和MARCKSL1基因；
所述儿童白血病预后风险评分模型包括AML模型、T-ALL模型和MPAL模型；
所述AML模型使用以下方程计算风险得分：
风险得分＝0.105225*CD69基因表达水平-0.0338431*CD99基因表达水平-0.0449341*TMSB4X基因表达水平-0.2092702*PLIN2基因表达水平-0.0675673*MARCKSL1基因表达水平+0.0002883*SOX4基因表达水平-0.0138693*KLF6基因表达水平-0.1168628*CD47基因表达水平+0.0287487*CORO1A基因表达水平；
所述T-ALL模型使用以下方程计算风险得分：
风险得分＝(-0.06924)*CD69基因表达水平+0.14446*CD99基因表达水平-0.31483*TMSB4X基因表达水平+0.21472*PLIN2基因表达水平+0.3215*MARCKSL1基因表达水平-0.25352*SOX4基因表达水平-0.03651*KLF6基因表达水平+0.3148*CD47基因表达水平+0.39645*CORO1A基因表达水平；
所述MPAL模型使用以下方程计算风险得分：
风险得分＝(-0.05335)*CD69基因表达水平-0.52334*CD99基因表达水平-0.24722*TMSB4X基因表达水平-0.54121*PLIN2基因表达水平-0.18649*MARCKSL1基因表达水平+0.24516*SOX4基因表达水平+0.77431*KLF6基因表达水平+0.15399*CD47基因表达水平+0.08337*CORO1A基因表达水平。
4.根据权利要求3所述的应用，其特征在于，根据所述评分结果预测儿童白血病患者预后的标准为：当评分结果为AML≥-0.01389317、T-ALL≥0.0190043且MPAL≥0.04315561的患者作为高危组，当评分结果为AML＜-0.01389317、T-ALL<0.0190043且MPAL<0.04315561的患者时作为低危组；所述高危组预后效果不佳。
5.根据权利要求3所述的应用，其特征在于，所述儿童白血病包括急性髓系白血病、急性淋巴细胞白血病和混合表型急性白血病。
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