De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes

Abstract

The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu.

AML‑derived mesenchymal stem cells upregulate CTGF expression through the BMP pathway and induce K562‑ADM fusiform transformation and chemoresistance

“…IL-6 and its downstream signaling molecules are responsible for multidrug resistance (72). Similarly, changes in IL-32 levels can alter the chemical protective effects of cells on cytarabine-induced apoptosis (20). In this study, our co-culture experiments further implicated the role of IL-6 and IL-32 in the development of chemoresistance as mediated by CTGF and the BMP pathway (Figs.…”

“…These defects in AML-MSCs are closely related to DNA methylation, transcriptional gene expression (18) and chromosomal aberrations (19). Additionally, compared with HD-MSCs, the significant changes in cytokines, such as interleukin (IL)-6 and IL-32 induced by AML-MSCs has been shown to be associated with chemoresistance (20). Collectively, the BMM constructed by AML-MSCs can be considered distinct from that of HD-MSCs.…”

Location First: Targeting Acute Myeloid Leukemia Within Its Niche

“…Moreover, Reikvam et al reported that primary AML cells co-cultured with healthy donor-derived MSCs induce an increment in IL-6 release into the media [91]. Furthermore, Lopes et al showed that the increased amount of IL-6 produced by MSCs is directly correlated with disease progression from myelodysplastic syndrome (MDS) to AML [92]. In contrast to this study, Kittang et al demonstrated that MDS patients display higher IL-6 production compared to healthy donors, but the authors did not find any correlation between IL-6 levels and progression to AML [93].…”

Bone marrow niches in myeloid neoplasms

“…As a result, AML cells modify the behavior of niche cells to an AML‐prone nature, thereby suppressing normal hematopoiesis and inducing the dominant proliferation of AML cells. Thus, the bone marrow microenvironments of MDS → OL (AML‐MRC) and de novo AML were found to be completely different from the normal functions of niche cells . In MDS bone marrow, CD34‐positive/c‐kit‐positive cells are generally located in proximity to CXCL12‐positive cells and express the BCL‐2 protein, resulting in the suppression of apoptosis.…”