Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
Oncogene. 2016 Sep 1;35(35):4591-600. doi: 10.1038/onc.2015.525. Epub 2016 Jan 25.
To improve treatment of acute lymphoblastic leukaemia (ALL), a better understanding of disease development is needed to tailor new therapies. Connective tissue growth factor (CTGF/CCN2) is highly expressed in leukaemia cells from the majority of paediatric patients with B-lineage ALL (pre-B ALL). CTGF is a matricellular protein and plays a role in aggressive cancers. Here we have genetically engineered leukaemia cells to modulate CTGF expression levels. Elevated CTGF levels accelerated disease dissemination and reduced survival in NOD/SCID mice. In vitro studies showed that CTGF protein induces stromal cell proliferation, promotes adhesion of leukaemia cells to stromal cells and leads to overexpression of genes associated with cell cycle and synthesis of extracellular matrix (ECM). Corresponding data from our leukaemia xenograft models demonstrated that CTGF leads to increased proliferation of non-leukaemia cells and deposition of ECM in the bone marrow. We document for the first time a functional role of CTGF in altering disease progression in a lymphoid malignancy. The findings provide support for targeting the bone marrow microenvironment in aggressive forms of leukaemia.
为了改善急性淋巴细胞白血病（ALL）的治疗效果，我们需要更好地了解疾病的发展，以便为新疗法提供依据。连接组织生长因子（CTGF/CCN2）在大多数儿童 B 系 ALL（前 B ALL）患者的白血病细胞中高度表达。CTGF 是一种基质细胞蛋白，在侵袭性癌症中发挥作用。在这里，我们通过基因工程手段调节白血病细胞中 CTGF 的表达水平。升高的 CTGF 水平加速了疾病的扩散，并降低了 NOD/SCID 小鼠的存活率。体外研究表明，CTGF 蛋白可诱导基质细胞增殖，促进白血病细胞与基质细胞的黏附，并导致与细胞周期和细胞外基质（ECM）合成相关的基因过表达。我们的白血病异种移植模型中的相应数据表明，CTGF 导致骨髓中非白血病细胞的增殖增加和 ECM 的沉积。我们首次证明 CTGF 在改变淋巴恶性肿瘤的疾病进展中具有功能作用。这些发现为靶向侵袭性白血病的骨髓微环境提供了依据。
