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(1), 1090. (doi: 10.1038/s41467-024-45471-0) (PMID:38316788) (PMCID:PMC10844594)

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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 Zarou, Martha-Maria and Kerekes, Zsombor and Helgason, Professor Vignir and Kirschner, Dr Kristina and Dawson, Ms Amy and Dunn, Mrs Karen and Zerbst, Désirée and Almasoudi, Hassan and Vetrie, Professor David and Hsieh, Dr Ya-Ching and Hopcroft, Dr Lisa and Copland, Professor Mhairi and Prasad, Dr Bodhayan and Wheadon, Professor Helen
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(1):1090
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
167847Autophagy Inhibition Combined with Targeted Therapy for Elimination of CML Stem Cells.Vignir HelgasonThe Kay Kendall Leukaemia Fund (KENDALL)KKL698School of Cancer Sciences
307077Targeting Autophagy and Aberrant Metabolism of Leukaemic Stem CellsVignir HelgasonCancer Research UK (CRUK)C57352/A29754SCS - Therapeutic Science Research