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

Abstract

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 demonstrates that TREM1 cooperates with diminished DNA damage response to induce expansion of pre-leukemic hematopoietic stem cells (HSCs) in mice deficient for the Fanconi anemia gene Fanca. Here we investigate TREM1 in leukemogenesis using mouse models of the DNA repair-deficient Fanca^-/- and the oncogenic MLL-AF9 or Kras^G12D. We found that Trem1 was highly expressed in pre-leukemic HSCs and leukemia stem cells (LSCs). By selective deletion of the Trem1 gene in the hematopoietic compartment, we showed that ablation of Trem1 reduced leukemogenic activity of the pre-leukemic HSCs and LSCs in mice. Trem1 was required for the proliferation of the pre-leukemic HSCs and LSCs. Further analysis revealed that Trem1 expression in pre-leukemic HSCs and LSCs was associated with persistent DNA damage, prolonged oncogenic stress, and a strong inflammatory signature. Targeting several top Trem1 inflammatory signatures inhibits the proliferation of pre-leukemic HSCs and LSCs. Collectively, our observations uncover previously unknown expression and function of TREM1 in malignant stem cells, and identify TREM1 as a driver of leukemogenesis.