MACROPHAGE INVOLVEMENT IN THE RESPONSE OF ACUTE MYELOID LEUKAEMIA TO CHEMOTHERAPY

In Acute myeloid leukaemia (AML) chemotherapy is usually effective at debulking AML blasts however a small population capable of re-initiating the leukaemia survive ultimately causing fatal relapse. Mouse models of AML suggest that these cells are protected from chemotherapy by a niche similar to hematopoietic stem cell (HSC) niches. As bone marrow (BM) macrophages are regulators of HSC niche function we investigated their potential role in promoting chemoresistance in AML. We first determined whether non-malignant BM macrophages were able to survive chemotherapy in mice. After chemotherapy we found the most resilient myeloid population in the BM to be the F4/80+ CD169+ macrophages. To investigate the role these chemotherapy-resilient CD169+ macrophages have in promoting chemoresistance to AML blasts, we transplanted MLL-AF9 leukaemia cells generated with wild-type HSCs into CD169DTR/WT mouse recipients. This enables specific depletion of non-malignant CD169+ macrophages in vivo via diphtheria toxin (DT) injection. In the absence of chemotherapy, depletion of CD169+ macrophages did not alter leukaemia burden in the BM, spleen or blood and did not alter mouse survival. However when chemotherapy was administered after DT administration, median survival of CD169-DTR recipients was significantly increased. Furthermore leukaemia burden in both the blood and spleen was significantly reduced. Interestingly using a full CD169 knockout mouse model did not alter mouse survival after chemotherapy. In conclusion, non-malignant CD169+ macrophages may protect MLL-AF9 leukaemia blasts from the cytotoxic effects of chemotherapy. The mechanisms of this chemoprotection remain to be determined but do not involve a direct effect of CD169.