Almeida Renata Santos, Gomes Thailany Thays, Araújo Felipe Souza, de Oliveira Sávio Augusto Vieira, Santos Jair Figueredo, Donadi Eduardo Antônio, Lucena-Silva Norma
Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Institute, Oswaldo Cruz Foundation (Fiocruz), Recife, Brazil.
Clinical Immunology Division, Department of Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil.
Front Genet. 2022 Jun 14;13:871972. doi: 10.3389/fgene.2022.871972. eCollection 2022.
HLA-G is a nonclassical histocompatibility class I molecule that plays a role in immune vigilance in cancer and infectious diseases. We previously reported that highly soluble HLA-G (sHLA-G) levels in the bone marrow were associated with a high blood cell count in T-acute lymphoblastic leukemia, a marker associated with a poor prognosis. To understand the posttranscriptional gene regulation in leukemia, we evaluated the bone marrow microRNA profile associated with the HLA-G bone marrow mRNA expression and sHLA-G bone marrow levels in children exhibiting acute leukemia (B-ALL, T-ALL, and AML) using massively parallel sequencing. Ten differentially expressed miRNAs were associated with high sHLA-G bone marrow levels, and four of them (hsa-miR-4516, hsa-miR-486-5p, hsa-miR-4488, and hsa-miR-5096) targeted , acting at distinct gene segments. For qPCR validation, these miRNA expression levels (ΔCt) were correlated with and mRNA expressions and sHLA-G bone marrow levels according to the leukemia subtype. The hsa-miR-4488 and hsa-miR-5096 expression levels were lower in B-ALL than in AML, while that of hsa-miR-486-5p was lower in T-ALL than in AML. In T-ALL, hsa-miR-5096 correlated positively with and negatively with sHLA-G. In addition, hsa-miR-4516 correlated negatively with sHLA-G levels. In AML, hsa-miR-4516 and hsa-miR-4488 correlated positively with mRNA, but the negatively correlated with sHLA-G. Our findings highlight the need to validate the findings of massively parallel sequencing since the experiment generally uses few individuals, and the same type of leukemia can be molecularly quite variable. We showed that miRNA's milieu in leukemia's bone marrow environment varies according to the type of leukemia and that the regulation of sHLA-G expression exerted by the same miRNA may act by a distinct mechanism in different types of leukemia.
HLA - G是一种非经典的I类组织相容性分子，在癌症和传染病的免疫监测中发挥作用。我们之前报道过，骨髓中高可溶性HLA - G（sHLA - G）水平与T急性淋巴细胞白血病的高血细胞计数相关，该血细胞计数是一个与预后不良相关的标志物。为了了解白血病中的转录后基因调控，我们使用大规模平行测序评估了患有急性白血病（B - 急性淋巴细胞白血病、T - 急性淋巴细胞白血病和急性髓系白血病）的儿童中与HLA - G骨髓mRNA表达和sHLA - G骨髓水平相关的骨髓微小RNA谱。十种差异表达的微小RNA与高sHLA - G骨髓水平相关，其中四种（hsa - miR - 4516、hsa - miR - 486 - 5p、hsa - miR - 4488和hsa - miR - 5096）靶向作用于不同的基因片段。为了进行qPCR验证，根据白血病亚型，这些微小RNA的表达水平（ΔCt）与[未提及的基因]和[未提及的基因]mRNA表达以及sHLA - G骨髓水平相关。hsa - miR - 4488和hsa - miR - 5096在B - 急性淋巴细胞白血病中的表达水平低于急性髓系白血病，而hsa - miR - 486 - 5p在T - 急性淋巴细胞白血病中的表达水平低于急性髓系白血病。在T - 急性淋巴细胞白血病中，hsa - miR - 5096与[未提及的基因]呈正相关，与sHLA - G呈负相关。此外，hsa - miR - 4516与sHLA - G水平呈负相关。在急性髓系白血病中，hsa - miR - 4516和hsa - miR - 4488与[未提及的基因]mRNA呈正相关，但[未提及的基因]与sHLA - G呈负相关。我们的研究结果强调了验证大规模平行测序结果的必要性，因为该实验通常使用的个体较少，并且同一类型的白血病在分子水平上可能差异很大。我们表明，白血病骨髓环境中的微小RNA环境因白血病类型而异，并且同一微小RNA对sHLA - G表达的调控在不同类型的白血病中可能通过不同的机制起作用。
