Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou.
Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140.
Haematologica. 2022 Nov 1;107(11):2576-2588. doi: 10.3324/haematol.2021.280404.
The immune receptor TREM1 (Triggering receptor expressed on myeloid cells 1) is a master regulator of inflammatory response. Compelling evidence suggests important pathological roles for TREM1 in various types of solid tumors. However, the role of TREM1 in hematologic malignancies is not known. Our previous study demonstrated that TREM1 cooperates with diminished DNA damage response to induce expansion of pre-leukemic hematopoietic stem cells (HSC) in mice deficient for the Fanconi anemia gene Fanca. Here we investigated TREM1 in leukemogenesis using mouse models of the DNA repair-deficient Fanca-/- and the oncogenic MLL-AF9 or KrasG12D. We found that Trem1 was highly expressed in preleukemic HSC and leukemia stem cells (LSC). By selective deletion of the Trem1 gene in the hematopoietic compartment, we showed that ablation of Trem1 reduced leukemogenic activity of the pre-leukemic HSC and LSC in mice. Trem1 was required for the proliferation of the pre-leukemic HSC and LSC. Further analysis revealed that Trem1 expression in preleukemic HSC and LSC was associated with persistent DNA damage, prolonged oncogenic stress, and a strong inflammatory signature. Targeting several top Trem1 inflammatory signatures inhibited the proliferation of pre-leukemic HSC and LSC. Collectively, our observations uncover previously unknown expression and function of TREM1 in malignant stem cells, and identify TREM1 as a driver of leukemogenesis.
TREM1（髓样细胞触发受体 1）是一种免疫受体，是炎症反应的主要调节因子。有强有力的证据表明，TREM1 在各种实体肿瘤中具有重要的病理作用。然而，TREM1 在血液恶性肿瘤中的作用尚不清楚。我们之前的研究表明，TREM1 与减弱的 DNA 损伤反应协同作用，诱导缺乏范可尼贫血基因 Fanca 的小鼠中的白血病前造血干细胞（HSC）扩增。在这里，我们使用 DNA 修复缺陷型 Fanca-/-小鼠和致癌性 MLL-AF9 或 KrasG12D 小鼠模型研究了 TREM1 在白血病发生中的作用。我们发现，Trem1 在白血病前 HSC 和白血病干细胞（LSC）中高度表达。通过在造血细胞中选择性缺失 Trem1 基因，我们表明 Trem1 缺失可降低小鼠白血病前 HSC 和 LSC 的白血病发生活性。Trem1 是白血病前 HSC 和 LSC 增殖所必需的。进一步的分析表明，白血病前 HSC 和 LSC 中的 Trem1 表达与持续的 DNA 损伤、延长的致癌应激和强烈的炎症特征有关。针对几个顶级 Trem1 炎症特征可抑制白血病前 HSC 和 LSC 的增殖。总之，我们的观察结果揭示了 TREM1 在恶性干细胞中以前未知的表达和功能，并将 TREM1 鉴定为白血病发生的驱动因素。
