# Role of LAM-specific TREM1 in leukemogenesis > **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $517,618 ## Abstract PROJECT SUMMARY/ABSTRACT Cancer progression is heavily influenced by supportive cells in the tumor microenvironment. Macrophages, an important component of tissue microenvironment, play important roles in both physiological and pathological processes. Macrophages that infiltrate into tumor tissues are regarded as tumor-associated macrophages (TAMs) or leukemia-associate macrophages (LAMs) in leukemia. Although a connection between LAMs and hematologic malignancies has long been appreciated, the molecular mechanism by which LAMs promote leukemogenesis is far less understood. We have employed Fanconi anemia (FA), a genetic disorder associated with bone marrow failure and progression to pre-leukemic myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), to study DNA damage-immune responses. Using the DNA damage-induced pre-leukemic mouse model deficient for the major FA gene Fanca (Fanca-/-) and the oncogenic MLL-AF9 AML model, we recently demonstrated that persistent DNA damage- and oncogenic stress-induced immune receptor TREM1 (CD354) promoted leukemia progression in mice. Compelling evidence suggests important pathological roles for TREM1 in various types of cancers, mainly linking to its upregulation and orchestrating inflammatory responses in TAMs. However, how TREM1 functions in leukemic microenvironment remains unclear. To exploit this, we generated a conditional Trem1 mouse model, with which we deleted the Trem1 gene specifically in macrophages using the LysM-Cre deleter strain. We found that macrophage-specific deletion of Trem1 markedly limited the expansion of Fanca-/- pre- leukemic HSCs and MLL-AF9 leukemic stem cells (LSCs) in Fanca-/- pre-leukemic and MLL-AF9 leukemia mice. More recently, we generated an inducible macrophage-specific Trem1-KO mouse model (Trem1fl/flCsf1r-iCre), and found that tamoxifen induction-mediated LAM-specific deletion of Trem1 altered the gene signatures of M1 and M2 macrophages and skewed macrophage polarization toward the M1-like status in both Fanca-/- and MLL- AF9 leukemia models. Stage-specific deletion of Trem1 significantly reduced PD-L1 expression in LAMs in these leukemia mice. We also found that TREM1+LAMs are required for stimulating the migration and expansion of LSCs in both Fanca-/- and MLL-AF9 leukemia models. Finally, TREM1+LAMs from AML patients were found to promote the engraftment of leukemic cells in a patient-derived xenograft (PDX) model. These preliminary studies establish a potential link between TREM1-positive LAMs and leukemia development. We hypothesize that TREM1-driven interactions between leukemia-associated macrophages and leukemia stem cells promote the development of leukemia. The goals of our study are to 1) examine the role of TREM1 within LAMs in leukemia development and to 2) investigate the functional interplays between TREM1+LAMs and LSCs. ## Key facts - **NIH application ID:** 10975114 - **Project number:** 1R01CA285400-01A1 - **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH - **Principal Investigator:** Wei Du - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $517,618 - **Award type:** 1 - **Project period:** 2024-08-09 → 2029-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10975114 ## Citation > US National Institutes of Health, RePORTER application 10975114, Role of LAM-specific TREM1 in leukemogenesis (1R01CA285400-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10975114. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*