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Leukaemia Exposure Alters the Transcriptional Profile and Function of BCR-ABL Negative Macrophages in the Bone Marrow Niche

ABSTRACT: Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis, fight infection and play roles in both anti-cancer immunity and tumour progression. However, the function of macrophages in myeloid leukaemias remains largely unknown due to difficulties in isolating non-transformed cells from those derived from the malignant clone. Here we use a state-of-the-art chimeric mouse model of chronic myeloid leukaemia (CML) to study the impact of the dysregulated bone marrow (BM) microenvironment on bystander macrophages. Utilising both single cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages and secretory proteomics of murine c-Kit+ stem/progenitor cells we have uncovered that macrophages exposed to a CML environment are altered transcriptionally and have reduced phagocytic function. Comparison of CML exposed macrophages to control counterparts by scRNA-seq has demonstrated significant heterogeneity in bone marrow (BM) macrophages, with the CML niche driving two unique subpopulations of immature and anti-inflammatory macrophages. Furthermore, we have identified that CML exposed macrophages can be separated from their normal counterparts via differential expression of surface markers CD36 and TGFBI, thereby providing us with a novel strategy to isolate Ph- macrophages in a CML BM niche. Finally, we have demonstrated that the dysregulated CML protein secretome is partially responsible for the in vivo alterations of macrophages, uncovering aberrant production of the immune modulatory protein lactotransferrin (LTF), and showing exposure to CML secreted factors suppresses phagocytosis, mitochondrial respiration, and inflammatory gene expression in BM macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE204978 | GEO | 2023/12/20

REPOSITORIES: GEO

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Project description:The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor that strongly associates with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (α-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and BCR-ABL1 mRNA levels, while α-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Microarray analysis of human CML- vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, further linking fibrosis to LSC persistence. Although we have not investigated whether MF is directly responsible for LSC persistence or whether it is merely an epiphenomenon occurring alongside the development of an LSC-supportive niche, we strongly believe that this is a mechanism that merits further investigation We used microarrays to compare MSCs expression profiles of HD vs. CML patients.

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Leukaemia Exposure Alters the Transcriptional Profile and Function of BCR-ABL Negative Macrophages in the Bone Marrow Niche

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