Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey.
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey.
Int J Radiat Oncol Biol Phys. 2020 Jul 15;107(4):779-792. doi: 10.1016/j.ijrobp.2020.03.026. Epub 2020 Apr 4.
Acquired hematopoietic failure is commonly caused by therapeutic and accidental exposure of the bone marrow (BM) to toxic agents. Efficient recovery from BM failure is dictated not only by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells but also by the BM environment niche. Identification of genetic factors that improve recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized and putatively nonhistone methyltransferase. This study aims to identify the roles of SETD4 in BM recovery.
An inducible SETD4 knockout mouse model (Setd4;Rosa26-CreERT2) was used. Adult sex-matched littermates were treated with tamoxifen to induce Setd4 deletion or oil as the control. Tamoxifen-treated Setd4;Rosa26-CreERT2 mice were included as another control. Those mice were irradiated to induce hematopoietic syndrome and analyzed to identify the roles and mechanisms of Setd4 in of BM recovery.
Loss of Setd4 in adult mice improved the survival of whole-body irradiation-induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSCs) and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to radiation resistance of the Setd4-deficient HSCs but that Setd4-deficient HSCs were actually more sensitive to radiation. However, the Setd4-deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was enhanced splenic erythropoiesis in Setd4-deficient mice.
These findings not only revealed a previously unrecognized role of Setd4 as a unique modulator of hematopoiesis but also underscored the critical role of the BM niche in recovery from hematopoietic failure. Our study also implicated Setd4 as a potential target for therapeutic inhibition to improve the conditioning of the BM niche before allogeneic transplantation.
获得性造血衰竭通常是由骨髓（BM）暴露于毒性物质引起的治疗性和意外性损伤所致。从骨髓衰竭中有效恢复不仅取决于造血干/祖细胞的固有敏感性和增殖能力，还取决于骨髓环境。鉴定可改善造血衰竭恢复的遗传因素至关重要。脊椎动物 SETD4 是一种特征不明显且假定的非组蛋白甲基转移酶。本研究旨在确定 SETD4 在 BM 恢复中的作用。
使用诱导型 SETD4 敲除小鼠模型（Setd4；Rosa26-CreERT2）。成年同窝配对的对照组接受他莫昔芬处理以诱导 Setd4 缺失或用油处理。将接受他莫昔芬处理的 Setd4；Rosa26-CreERT2 小鼠作为另一个对照组。这些小鼠接受辐射以诱导造血综合征，并分析以确定 Setd4 在 BM 恢复中的作用和机制。
成年小鼠中 Setd4 的缺失改善了全身照射诱导的 BM 衰竭的生存。这与长期和短期造血干细胞（HSCs）和早期祖细胞的恢复改善相关。BM 移植分析令人惊讶地表明，改善的恢复不是由于 Setd4 缺陷 HSCs 的辐射抗性所致，而是 Setd4 缺陷 HSCs 实际上对辐射更敏感。然而，Setd4 缺陷小鼠是同种异体 HSC 移植的更好接受者。此外，Setd4 缺陷小鼠的脾脏红细胞生成增强。
这些发现不仅揭示了 Setd4 作为造血独特调节剂的先前未知作用，还强调了骨髓龛在造血衰竭恢复中的关键作用。我们的研究还暗示 Setd4 可能是一种潜在的治疗靶点，用于在同种异体移植前抑制骨髓龛以改善其条件。
