Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche

• Published in: Nature communications Vol. 15; no. 1; p. 1090
• Main Authors: Dawson, Amy, Zarou, Martha M., Prasad, Bodhayan, Bittencourt-Silvestre, Joana, Zerbst, Désirée, Himonas, Ekaterini, Hsieh, Ya-Ching, van Loon, Isabel, Blanco, Giovanny Rodriguez, Ianniciello, Angela, Kerekes, Zsombor, Krishnan, Vaidehi, Agarwal, Puneet, Almasoudi, Hassan, McCluskey, Laura, Hopcroft, Lisa E. M., Scott, Mary T., Baquero, Pablo, Dunn, Karen, Vetrie, David, Copland, Mhairi, Bhatia, Ravi, Coffelt, Seth B., Tiong, Ong Sin, Wheadon, Helen, Zanivan, Sara, Kirschner, Kristina, Helgason, G. Vignir
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-02-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/100; 13/106; 13/109; 13/2; 13/31; 13/44; 13/89; 38/39; 631/250/2504/342; 631/250/262; 631/250/580; 631/67/1990/283/1896; 631/80; Animals; Apoptosis; Bone marrow; Bone Marrow - pathology; CD36 antigen; Cell differentiation; Chronic myeloid leukemia; Clearances; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Gene sequencing; Hemopoiesis; Humanities and Social Sciences; Humans; Immune clearance; Immune system; Innate immunity; Lactoferrin; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemia, Myeloid - pathology; Macrophages; Macrophages - metabolism; Mice; Microenvironments; multidisciplinary; Phagocytosis; Philadelphia Chromosome; Science; Science (multidisciplinary); Subpopulations; Surface markers; Transformed cells; Tumor Microenvironment - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45471-0

Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages.
The function of macrophages in myeloid leukaemia can be difficult to assess because of lack of differentiation between transformed and non-transformed cells. Here the authors use a chimeric mouse model to characterise the effect of myeloid leukaemia on bystander macrophages noting altered functional properties of these cells.