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Chữ ký phiên mã của gia đình BCL2 cho liệu pháp điều trị bệnh bạch cầu tủy cấp tính cá thể hóa
Tóm tắt
Mặc dù các protein chống apoptosis của gia đình B-cell lymphoma-2 (BCL2) đã được sử dụng như những mục tiêu điều trị trong bệnh bạch cầu tủy cấp tính (AML), nhưng mạng lưới điều chỉnh phức tạp của chúng khiến cho việc điều trị cá thể hóa trở nên khó khăn. Nghiên cứu này nhằm phát hiện các chữ ký phiên mã của các gen gia đình BCL2 phản ánh sự động học điều chỉnh, có thể hướng dẫn các chiến lược điều trị cá thể hóa. Từ ba nhóm RNA-seq AML (BeatAML, LeuceGene, và TCGA; n = 451, 437 và 179, tương ứng), chúng tôi đã xây dựng các chữ ký gia đình BCL2 (BFSigs) bằng cách áp dụng một phương pháp lựa chọn bộ gen sáng tạo phản ánh kiến thức sinh học, sau đó là phân tích ma trận phi âm (NMF). Để chứng minh tầm quan trọng của BFSigs, chúng tôi đã thực hiện mô hình để dự đoán phản ứng đối với các chất ức chế gia đình BCL2, phân cụm, và phân tích làm giàu chức năng. Tính hợp lệ của BFSigs giữa các nền tảng cũng đã được xác nhận bằng công nghệ NanoString trong một nhóm bệnh nhân riêng biệt gồm 47 người. Chúng tôi đã thiết lập các BFSigs được gán nhãn là chữ ký BCL2, MCL1/BCL2 và BFL1/MCL1, xác định các protein chống apoptosis chính. Phân cụm không giám sát dựa trên thông tin BFSig đã phân loại nhất quán bệnh nhân AML thành ba kiểu con vững chắc trên các nhóm AML khác nhau, ngụ ý sự tồn tại của các thực thể sinh học được tiết lộ bởi phương pháp BFSig. Thú vị thay, mỗi kiểu con có các mẫu làm giàu khác biệt của các con đường ung thư chính, bao gồm MAPK và mTORC1, điều này đề xuất liệu pháp kết hợp đặc thù kiểu con với các loại thuốc điều chỉnh apoptosis. Bộ phân loại dựa trên BFSig cũng dự đoán phản ứng đối với venetoclax với hiệu suất đáng kể (diện tích dưới đường cong ROC, AUROC = 0.874), điều này đã được xác nhận tốt trong một nhóm độc lập (AUROC = 0.950). Cuối cùng, chúng tôi đã xác nhận thành công tính hợp lệ của BFSigs bằng công nghệ NanoString. Nghiên cứu này đề xuất BFSigs như một sinh phẩm để lựa chọn hiệu quả các liệu pháp điều trị nhắm vào apoptosis và các con đường ung thư để cùng nhắm đến trong AML.
Từ khóa
#BCL2 #bệnh bạch cầu tủy cấp tính #liệu pháp điều trị cá thể hóa #chữ ký phiên mã #các protein chống apoptosisTài liệu tham khảo
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