GPRASP 蛋白缺乏会影响 B 细胞分化,从而引发淋巴组织增生性疾病。

IF 7.6 2区 医学 Q1 HEMATOLOGY HemaSphere Pub Date : 2024-10-30 DOI:10.1002/hem3.70037
Antonio Morales-Hernández, Emilia Kooienga, Heather Sheppard, Gabriela Gheorghe, Claire Caprio, Ashley Chabot, Shannon McKinney-Freeman
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引用次数: 0

摘要

Gprasp1和Gprasp2编码控制CXCR4稳定性和细胞贩运的蛋白质,CXCR4是造血的主调节因子,B细胞在生殖中心(GC)的适当贩运需要它的动态调节。在这里,我们报告了 Gprasp1 和 Gprasp2 缺陷的 B 细胞在 GC 中聚集并显示出转录异常,影响了控制 Aicda 表达的机制,并使它们面临过度的体细胞超突变。因此,在移植了Gprasp缺陷造血干细胞和祖细胞的小鼠中,约有30%的小鼠在移植后20-50周出现了生物侵袭性和致命的B细胞过度增殖性疾病。组织学和分子谱分析显示,Gprasp1和Gprasp2缺陷型肿瘤在形态上类似于人类生殖中心起源的高级别B细胞淋巴瘤,具有伯基特淋巴瘤(BL)和弥漫大B细胞淋巴瘤(DLBCL)的共同形态特征,分子特征与DLBCL一致,以及突变负荷增加和异源转录与突变特征。因此,Gprasp1 和 Gprasp2 基因表达的减少会扰乱 B 细胞的成熟,并增加生殖中心来源 B 细胞肿瘤的风险。由于该模型再现了人类异质性造血恶性肿瘤的基本特征,因此它可以成为研究这些癌症淋巴致病机制的有力工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation

Gprasp1 and Gprasp2 encode proteins that control the stability and cellular trafficking of CXCR4, a master regulator of hematopoiesis whose dynamic regulation is required for appropriate trafficking of B-cells in the germinal center (GC). Here, we report that Gprasp1 and Gprasp2-deficient B-cells accumulate in the GC and show transcriptional abnormalities, affecting the mechanisms controlling Aicda expression and exposing them to excessive somatic hypermutation. Consequently, about 30% of mice transplanted with Gprasp-deficient hematopoietic stem and progenitor cells developed a biologically aggressive and fatal B-cell hyperproliferative disease by 20–50 weeks posttransplant. Histological and molecular profiling reveal that Gprasp1- and Gprasp2-deficient neoplasms morphologically resemble human high-grade B-cell lymphomas of germinal center origin with shared morphologic features of both Burkitt Lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), and molecular features consistent with DLBCL, as well as elevated mutational burden and heterogenous transcriptional and mutational signature. Thus, reduced Gprasp1 and Gprasp2 gene expression perturbs B-cell maturation and increases the risk of B-cell neoplasms of germinal center origin. As this model recapitulates the essential features of the heterogenous group of human hematopoietic malignancies, it could be a powerful tool to interrogate the mechanisms of lymphomagenesis for these cancers.

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来源期刊
HemaSphere
HemaSphere Medicine-Hematology
CiteScore
6.10
自引率
4.50%
发文量
2776
审稿时长
7 weeks
期刊介绍: HemaSphere, as a publication, is dedicated to disseminating the outcomes of profoundly pertinent basic, translational, and clinical research endeavors within the field of hematology. The journal actively seeks robust studies that unveil novel discoveries with significant ramifications for hematology. In addition to original research, HemaSphere features review articles and guideline articles that furnish lucid synopses and discussions of emerging developments, along with recommendations for patient care. Positioned as the foremost resource in hematology, HemaSphere augments its offerings with specialized sections like HemaTopics and HemaPolicy. These segments engender insightful dialogues covering a spectrum of hematology-related topics, including digestible summaries of pivotal articles, updates on new therapies, deliberations on European policy matters, and other noteworthy news items within the field. Steering the course of HemaSphere are Editor in Chief Jan Cools and Deputy Editor in Chief Claire Harrison, alongside the guidance of an esteemed Editorial Board comprising international luminaries in both research and clinical realms, each representing diverse areas of hematologic expertise.
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