Persistent DNA damage and oncogenic stress-induced Trem1 promotes leukemia in mice

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 pre-leukemic 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.

Automated summary

Our study reveals the important role of TREM1 in leukemogenesis. Selective deletion of Trem1 in the hematopoietic compartment reduces the leukemogenic activity of leukemia stem cells. Trem1 expression is associated with DNA damage, oncogenic stress, and inflammatory signature. Inhibiting Trem1 inflammatory responses can reduce the proliferation of leukemia stem cells.