Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities

Abstract

Mesenchymal stromal cells (MSCs) are essential elements of the bone marrow (BM) microenvironment, which have been widely implicated in pathways that contribute to leukemia growth and resistance. Recent reports showed genotypic and phenotypic alterations in leukemia patient-derived MSCs, indicating that MSCs might be educated/reprogrammed. However, the results have been inconclusive, possibly due to the heterogeneity of leukemia. Here, the authors report that acute myeloid leukemia (AML) induces MSCs towards an adipogenic differentiation propensity. RNAseq analysis reveal significant upregulation of gene expression enriched in the adipocyte differentiation process and reduction in osteoblast differentiation. The alteration is accompanied by a metabolic switch from glycolysis to a more oxidative phosphorylation-dependent manner. Mechanistic studies identify that AML cell-derived exosomes play a vital role during the AML cell-mediated MSCs education/reprogramming process. Pre-administration of mice BM microenvironment with AML-derived exosomes greatly enhance leukemia engraftment in vivo. The quantitative proteomic analysis identified a list of exosomal protein components that are differently expressed in AML-derived exosomes, which represent an opportunity for novel therapeutic strategies based on the targeting of exosome-based AML cells-MSCs communication. Collectively, the data show that AML-educated MSCs tend to differentiate into adipocytes contributing to disease progression, which suggests complex interactions of leukemia with microenvironment components.

Drug Resistance: The Role of Exosomal miRNA in the Microenvironment of Hematopoietic Tumors

“…The progression of leukemia is guaranteed by the exosomes produced by the AML cells that facilitate the engraftment of AML and allow the communication of leukemia cells with their microenvironment, as well as inducing oncogenic factors such as c-Myc. [25,28]. Furthermore, the release of exosomes leads to the production of immune-inhibiting cytokines, thus ensuring the growth and survival of cancer cells.…”

Lipotoxicity as a Barrier for T Cell-Based Therapies

“…Leukemic cells and leukemic stem cells reside in the bone marrow and lymphatic niches that resemble a glucose-deprived and hypoxic TME, which is comparable to the conditions seen in solid tumors. Two recent studies demonstrated that acute myeloid leukemia (AML) cells remodel their direct environment by secretion of exosomes that, in turn, promote MSC differentiation towards adipocytes and lipolysis in already differentiated adipocytes [ 56 , 57 ]. Moreover, adipose tissue is beneficial for AML blasts and leukemic stem cells (LSCs) by increasing FAO and CD36/FABP4 expression, resulting in the prevention of serum starvation-induced apoptosis and protection from chemotherapy [ 58 , 59 ].…”

Over expression of ubiquitin‐conjugating enzyme E2O in bone marrow mesenchymal stromal cells partially attenuates acute myeloid leukaemia progression

“…It was reported that the bone marrow (BM) microenvironment could be remodelled into a hospitable niche supporting leukaemogenesis and impeding normal haematopoiesis in leukaemias 2,3 . BM mesenchymal stromal cells (BM‐MSCs), a heterogeneous, essential population of the BM niche, are reported to play different roles in the AML BM niche 4–6 . Zhang et al 4 reported that AML induced MSCs towards an adipogenic differentiation propensity, leading to greatly enhance leukaemia engraftment, which represented an opportunity for novel therapeutic strategies based on targeting AML cells–MSCs communication.…”

“…BM mesenchymal stromal cells (BM‐MSCs), a heterogeneous, essential population of the BM niche, are reported to play different roles in the AML BM niche 4–6 . Zhang et al 4 reported that AML induced MSCs towards an adipogenic differentiation propensity, leading to greatly enhance leukaemia engraftment, which represented an opportunity for novel therapeutic strategies based on targeting AML cells–MSCs communication. Another two studies also found that AML cells establish physical connections with MSCs facilitating leukaemia progression 5,6 .…”