Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Small GTPases. 2022 Jan;13(1):267-281. doi: 10.1080/21541248.2021.2019503.
RHOH/TFF, a member of the RAS GTPase super family, has important functions in lymphopoiesis and proximal T cell receptor signalling and has been implicated in a variety of leukaemias and lymphomas. RHOH was initially identified as a translocation partner with BCL-6 in non-Hodgkin lymphoma (NHL), and aberrant somatic hypermutation (SHM) in the 5' untranslated region of the RHOH gene has also been detected in Diffuse Large B-Cell Lymphoma (DLBCL). Recent data suggest a correlation between RhoH expression and disease progression in Acute Myeloid Leukaemia (AML). However, the effects of RHOH mutations and translocations on RhoH expression and malignant transformation remain unknown. We found that aged Rhoh (KO) mice had shortened lifespans and developed B cell derived splenomegaly with an increased Bcl-6 expression profile in splenocytes. We utilized a murine model of Bcl-6 driven DLBCL to further explore the role of RhoH in malignant behaviour by crossing Rhoh mice with Iµ-HABcl-6 transgenic (Bcl-6) mice. The loss of Rhoh in Bcl-6 mice led to a more rapid disease progression. Mechanistically, we demonstrated that deletion of Rhoh in these murine lymphoma cells was associated with decreased levels of the RhoH binding partner KAISO, a dual-specific Zinc finger transcription factor, de-repression of KAISO target Bcl-6, and downregulation of the BCL-6 target Blimp-1. Re-expression of RhoH in RhohBcl-6 lymphoma cell lines reversed these changes in expression profile and reduced proliferation of lymphoma cells in vitro. These findings suggest a previously unidentified regulatory role of RhoH in the proliferation of tumour cells via altered BCL-6 expression. (250).
RHOH/TFF，RAS GTPase 超级家族的成员，在淋巴发生和近端 T 细胞受体信号转导中具有重要功能，并与多种白血病和淋巴瘤有关。RHOH 最初被鉴定为非霍奇金淋巴瘤（NHL）中与 BCL-6 的易位伙伴，并且在弥漫性大 B 细胞淋巴瘤（DLBCL）中也检测到 RHOH 基因 5'非翻译区的异常体细胞超突变（SHM）。最近的数据表明，RhoH 表达与急性髓细胞白血病（AML）的疾病进展之间存在相关性。然而，RHOH 突变和易位对 RhoH 表达和恶性转化的影响仍不清楚。我们发现，衰老的 Rhoh（KO）小鼠的寿命缩短，并发展为 B 细胞来源的脾肿大，脾细胞中 Bcl-6 表达谱增加。我们利用 Bcl-6 驱动的 DLBCL 的小鼠模型，通过将 Rhoh 小鼠与 Iµ-HABcl-6 转基因（Bcl-6）小鼠杂交，进一步探讨 RhoH 在恶性行为中的作用。在 Bcl-6 小鼠中缺失 Rhoh 导致疾病进展更快。从机制上讲，我们证明这些小鼠淋巴瘤细胞中 Rhoh 的缺失与 RhoH 结合伙伴 KAISO 的水平降低有关，KAISO 是一种双特异性锌指转录因子，KAISO 的靶基因 Bcl-6 去抑制，以及 BCL-6 的靶基因 Blimp-1 下调。在 RhohBcl-6 淋巴瘤细胞系中重新表达 Rhoh 逆转了这些表达谱的变化，并减少了淋巴瘤细胞在体外的增殖。这些发现表明，RhoH 通过改变 BCL-6 表达在肿瘤细胞增殖中具有以前未被识别的调节作用。（250）。
