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

Dawson, A. et al. (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15, 1090. (doi: 10.1038/s41467-024-45471-0) (PMID:38316788) (PMCID:PMC10844594)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was supported by Friends of the Paul O’Gorman Leukaemia Research Centre (A.D., G.V.H., J.S., Z.K.), The Howat Foundation (G.V.H.), The Kay Kendall Leukaemia Fund (KKL698, P.B., G.V.H.), Tenovus Scotland (A.I., G.V.H.), Cancer Research UK (A29800 to S.Z. and A29754 to G.V.H.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Coffelt, Professor Seth and Zanivan, Professor Sara and Scott, Dr Mary and Ianniciello, Ms Angela and Baquero, Dr Pablo and Kerekes, Zsombor and Zarou, Martha-Maria and Helgason, Professor Vignir and Kirschner, Dr Kristina and Dunn, Mrs Karen and Dawson, Ms Amy and Zerbst, Désirée and Vetrie, Professor David and Almasoudi, Hassan and Hsieh, Dr Ya-Ching and Copland, Professor Mhairi and Hopcroft, Dr Lisa and Wheadon, Professor Helen and Prasad, Dr Bodhayan
• Authors: Dawson, A., Zarou, M. M., Prasad, B., Bittencourt-Silvestre, J., Zerbst, D., Himonas, E., Hsieh, Y.-C., van Loon, I., Rodriguez Blanco, G., Ianniciello, A., Kerekes, Z., Krishnan, V., Agarwal, P., Almasoudi, H., McCluskey, L., Hopcroft, L. E.M., Scott, M. T., Baquero, P., Dunn, K., Vetrie, D., Copland, M., Bhatia, R., Coffelt, S. B., Tiong, O. S., Wheadon, H., Zanivan, S., Kirschner, K., and Helgason, G. V.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2024 The Authors
• First Published: First published in Nature Communications 15: 1090
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
167847		Autophagy Inhibition Combined with Targeted Therapy for Elimination of CML Stem Cells.	Vignir Helgason	The Kay Kendall Leukaemia Fund (KENDALL)	KKL698	School of Cancer Sciences
307077		Targeting Autophagy and Aberrant Metabolism of Leukaemic Stem Cells	Vignir Helgason	Cancer Research UK (CRUK)	C57352/A29754	SCS - Therapeutic Science Research