Department of Anatomy, University of California, San Francisco, San Francisco, California USA.
Small GTPases. 2022 Jan;13(1):7-13. doi: 10.1080/21541248.2021.1882832. Epub 2021 Feb 10.
T-cell acute lymphoblastic leukaemia (T-ALL) is a bone marrow (BM) malignancy affecting children and adults. Typically treated with chemotherapy, leukaemia remains a major death cause in people under 20 years old. Understanding molecularly altered pathways in T-ALL may lead to new therapeutic avenues in the future. Ras pathway dysregulation is common in T-ALL. We have shown elevated expression levels of the Ras guanine nucleotide exchange factor RasGRP1 in T-ALL patients, which results in constant production of active Ras (RasGTP). When leukaemia cell lines are exposed to cytokines, RasGTP levels further increase in a RasGRP1-dependent manner. How overexpressed RasGRP1 may impact primary BM cells has remained unknown. We recently published a new mouse model that allows for pIpC-induced overexpression of RasGRP1 in haematopoietic cells, which can be traced with an ires-EGFP cassette. This novel model revealed that RasGRP1 overexpression bestows a fitness advantage to haematopoietic stem cells (HSCs) over wild-type cells. Intriguingly, this increased fitness only manifests in native Hematopoiesis, and not in BM transplantation (BMT) assays. In this commentary, we summarize key features of our model, elaborate on BM niche importance, and discuss differences between native Hematopoiesis and BMT in the context of stem cell metabolism.
T 细胞急性淋巴细胞白血病（T-ALL）是一种骨髓（BM）恶性肿瘤，可影响儿童和成人。通常采用化疗进行治疗，但白血病仍然是 20 岁以下人群的主要死亡原因。了解 T-ALL 中分子改变的途径可能会为未来带来新的治疗途径。Ras 通路失调在 T-ALL 中很常见。我们已经在 T-ALL 患者中显示出 Ras 鸟嘌呤核苷酸交换因子 RasGRP1 的表达水平升高，这导致活性 Ras（RasGTP）的持续产生。当白血病细胞系暴露于细胞因子时，RasGTP 水平会以 RasGRP1 依赖的方式进一步增加。过表达的 RasGRP1 如何影响原代 BM 细胞仍不清楚。我们最近发表了一种新的小鼠模型，该模型允许在造血细胞中通过 pIpC 诱导 RasGRP1 的过表达，并带有一个 ires-EGFP 盒进行追踪。该新型模型表明，RasGRP1 的过表达赋予造血干细胞（HSCs）相对于野生型细胞的适应性优势。有趣的是，这种适应性优势仅在天然造血中表现出来，而在骨髓移植（BMT）实验中则没有。在这篇评论中，我们总结了我们模型的关键特征，详细阐述了 BM 龛位的重要性，并讨论了在干细胞代谢的背景下，天然造血与 BMT 之间的差异。
