Poster Presentation 38th Lorne Cancer Conference 2026

Targeting macrophage-specific vulnerabilities to reduce relapse following AML differentiation therapy. (#265)

Jake H Tremewen 1 , Samin Iranfar 1 , Steven Ngo 1 , Ethan P Oxley 1 , Daniel Neville 1 , Daniel T Ferguson 1 , Omer Gilan 1 , Inês Barbosa 2 , Johannes Zuber 2 , Ross A Dickins 1
  1. ACBD, Monash University, Melbourne, Victoria, Australia
  2. Research Institute of Molecular Pathology, Vienna, Austria

Acute myeloid leukaemia (AML) is an aggressive disease characterised by the uncontrolled proliferation of myeloid blasts. AML is driven by class I pro-proliferative mutations and class II differentiation blocking mutations. Class II mutations are often mutually exclusive1, and alleviating these mutations can facilitate leukaemic differentiation and clearance. Differentiation therapies targeting these mutations offer a promising alternative to chemotherapy, yet clinical success can be limited by post‑remission relapse. Previous research from our lab using a genetic model of AML has highlighted an ability for mature AML‑derived populations to de‑differentiate to an immature leukaemogenic state2, 3. Inhibiting the emergence of the persistent AML-derived lineage in this model led to a reduction in relapse in vivo, implicating mature AML-derived populations as a potential source of relapse. Here we used a murine model of AML driven by a class I NRAS mutation and a Dox‑suppressible class II MLL‑AF9 oncogene to investigate the AML differentiation therapy response. Suppression of MLL‑AF9 leads to bulk maturation toward short‑lived AML‑derived neutrophils or long-lived AML‑derived macrophages both in vitro and in vivo. We hypothesise that AML‑derived macrophages may contribute to relapse following differentiation therapy. We conducted a whole genome CRISPR screen to identify specific genetic dependencies in AML-derived neutrophils and AML‑derived macrophages. This identified 77 genes specifically required for AML-derived macrophages. We aim to further characterise changes in the AML differentiation response following knockout of these genetic dependencies in vitro and in vivo. We anticipate that these newly identified macrophage-specific dependencies may represent therapeutically actionable targets when combined with differentiation therapy. We have also recently developed a Trp53 mutant in vivo AML model that rapidly and consistently relapses in vivo following differentiation therapy. Using this model we aim to assess whether depletion of AML-derived macrophages translates to reduced relapse.

  1. Metzeler KH, Herold T, Rothenberg-Thurley M, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128(5):686-698. doi:10.1182/blood-2016-01-693879
  2. McKenzie MD, Ghisi M, Oxley EP, et al. Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia. Cell Stem Cell. 2019;25(2):258-272.e9. doi:10.1016/j.stem.2019.07.001
  3. Ngo S, Oxley EP, Ghisi M, et al. Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy. Nat Commun. 2021;12(1):6546. Published 2021 Nov 11. doi:10.1038/s41467-021-26849-w