Nras Q61R/+Kras −/− phối hợp để giảm mức Rasgrp1 và thúc đẩy bệnh bạch cầu lympho-tủy trong các tiền tế bào T sớm

Blood - Tập 137 - Trang 3259-3271 - 2021
Zhi Wen1, Grant Yun1,2, Alexander Hebert3, Guangyao Kong1, Erik A. Ranheim4, Remington Finn1,2, Adhithi Rajagoplan5,6, Shuyi Li5, Yun Zhou1, Mei Yu7, Alisa Damnernsawad1, Jeroen P. Roose8, Joshua J. Coon3,9,10, Renren Wen7, Demin Wang7, Jing Zhang1
1McArdle Laboratory for Cancer Research, University of Wisconsin–Madison, Madison, WI
2Department of Biochemistry, University of Wisconsin–Madison, Madison, WI
3National Center for Quantitative Biology of Complex Systems, University of Wisconsin–Madison, Madison, WI
4Department of Pathology & Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center, Madison, WI
5McArdle Laboratory for Cancer Research, University of Wisconsin- Madison, Madison, WI
6Cellular and Molecular Biology Program, University of Wisconsin–Madison, Madison, WI
7Blood Research Institute, Versiti, Milwaukee, WI
8Department of Anatomy, University of California San Francisco, San Francisco, CA
9Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, WI
10Department of Chemistry, University of Wisconsin–Madison, Madison, WI

Tóm tắt

Tóm tắt

Bệnh bạch cầu lymphoblast ác tính tiền tế bào T sớm (ETP-ALL) là một trong những dạng ác tính mạnh của bạch cầu T. Mặc dù các đột biến gen làm tăng cường hoạt động của thụ thể cytokine/Ras phổ biến trong ETP-ALL, nhưng vẫn chưa biết làm thế nào mà hoạt động của tín hiệu Ras lại góp phần vào ETP-ALL. Tại đây, chúng tôi phát hiện rằng ngoài các đột biến RAS gây ung thư thường gặp, mức độ sao chép KRAS kiểu hoang dã (WT) bị giảm đáng kể trong các tế bào ETP-ALL của người. Tương tự, sự mất mát của WT Kras trong các chuột NrasQ61R/+ đã thúc đẩy sự siêu hoạt của tín hiệu kinase được điều chỉnh bởi tín hiệu ngoại bào (ERK), sự siêu tăng sinh của thymocyte và mở rộng của ngăn ETP. Các chuột Kras−/−; NrasQ61R/+ phát triển bệnh bạch cầu T đến sớm, mô hình hóa nhiều đặc điểm sinh học và phân tử của ETP-ALL ở người. Về cơ chế, phân tích RNA-sequencing và nghiên cứu proteomics định lượng đã xác định rằng Rasgrp1, một yếu tố trao đổi nucleotide guanine Ras, đã bị giảm đáng kể trong ETP-ALL ở chuột và người. Điều bất ngờ là, tín hiệu Nras/ERK siêu hoạt đã ức chế sự biểu hiện của Rasgrp1 và mức Rasgrp1 giảm dẫn đến tăng cường tín hiệu ERK, do đó thiết lập một vòng phản hồi tích cực để tăng cường tín hiệu Nras/ERK và thúc đẩy sự tăng trưởng tế bào. Hỗ trợ cho dữ liệu từ dòng tế bào của chúng tôi, sự thiếu hụt một bản sao Rasgrp1 đã gây ra sự giảm bớt Rasgrp1 và làm tăng mức độ ERK đã phosphoryl hóa và sự mở rộng ETP trong các chuột NrasQ61R/+. Nghiên cứu của chúng tôi xác định Rasgrp1 như một yếu tố điều hòa âm của tín hiệu Ras/ERK trong bệnh bạch cầu ETP giống như do Nras thúc đẩy.

Từ khóa


Tài liệu tham khảo

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