Poster Presentation 37th Lorne Cancer Conference 2025

Lineage-restricted differentiation therapy of acute myeloid leukaemia (#154)

Samin Iranfar 1 , Jake H. Tremewen 1 , Steven Ngo 1 , Johannes Zuber 2 , Ethan P. Oxley 1 , Ross A. Dickins 1
  1. Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia
  2. Research Institute of Molecular Pathology, Vienna, Austria

Acute myeloid leukaemia (AML) is a haematological malignancy caused by oncogenic mutations that drive aberrant proliferation and block maturation of self-renewing myeloid progenitors.1 In contrast to standard cytotoxic chemotherapy, differentiation therapies specifically target molecular differentiation blocks in immature AML blasts to induce their maturation and promote subsequent clearance by natural mechanisms. Despite the emergence of differentiation therapies, the rate of relapse in AML patients remains a consistent clinical challenge, highlighting the importance of therapies targeting potential sources of relapse. Most differentiation therapies rely on irreversible maturation of leukemic progenitors, however recent studies have demonstrated maturation state plasticity of AML cells whereby persistent mature AML-derived cells can regain leukemogenicity through de-differentiation, seeding relapse.2 Our laboratory has previously shown that AML blasts can undergo multi-lineage differentiation and whilst short-lived lineages such as neutrophils are rapidly cleared, specific persistent sub-lineages can de-differentiate and cause relapse.3 To investigate strategies to prevent relapse following AML differentiation therapy, we utilized a MLL-AF9-driven mouse model of AML. In this model, in vitro or in vivo differentiation therapy triggers lineage bifurcation, producing a short-lived population of AML-derived neutrophils and a persistent population of AML-derived macrophages. Given the known role of haematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) in instructing neutrophil lineage choice of normal myeloid progenitors, we aimed to interrogate its instructive potential in restricting AML blast differentiation into short-lived neutrophils. We have observed that even very low concentrations of G-CSF can accelerate in vitro clearance of mature AML-derived cells by favouring therapy-induced neutrophil lineage fate. Prolonged G-CSF administration prior to differentiation therapy enhances skewing towards the short-lived neutrophil lineage, reducing persistent AML-derived macrophages. Further work aims to characterize the molecular mechanism of G-CSF lineage restriction and its effects on differentiation therapy-induced AML clearance, residual disease phenotype, and relapse in vivo. These findings support the use of specific cytokines alongside differentiation therapies to alter multi-lineage differentiation and eradicate mature AML-derived cells to mitigate relapse.

  1. Bonnet, D. & Dick, J. E. Human acute myeloid leukaemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3, 730-737, doi:10.1038/nm0797-730 (1997)
  2. McKenzie, M. D. et al. Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukaemia. Cell Stem Cell 25, 258-272 e259, doi:10.1016/j.stem.2019.07.001 (2019).
  3. Ngo, S. et al. Acute myeloid leukaemia maturation lineage influences residual disease and relapse following differentiation therapy. Nat Commun 12, 6546, doi:10.1038/s41467-021-26849-w (2021).