Mesenchymal Stem Cells Support Survival and Proliferation of Primary Human Acute Myeloid Leukemia Cells through Heterogeneous Molecular Mechanisms

Abstract

Acute myeloid leukemia (AML) is a bone marrow malignancy, and various bone marrow stromal cells seem to support leukemogenesis, including osteoblasts and endothelial cells. We have investigated how normal bone marrow mesenchymal stem cells (MSCs) support the in vitro proliferation of primary human AML cells. Both MSCs and primary AML cells show constitutive release of several soluble mediators, and the mediator repertoires of the two cell types are partly overlapping. The two cell populations were cocultured on transwell plates, and MSC effects on AML cells mediated through the local cytokine/soluble mediator network could thus be evaluated. The presence of normal MSCs had an antiapoptotic and growth-enhancing effect on primary human AML cells when investigating a group of 51 unselected AML patients; this was associated with increased phosphorylation of mTOR and its downstream targets, and the effect was independent of cytogenetic or molecular-genetic abnormalities. The MSCs also supported the long-term proliferation of the AML cells. A subset of the patients also showed an altered cytokine network with supra-additive levels for several cytokines. The presence of cytokine-neutralizing antibodies or receptor inhibitors demonstrated that AML cells derived from different patients were heterogeneous with regard to effects of various cytokines on AML cell proliferation or regulation of apoptosis. We conclude that even though the effects of single cytokines derived from bone marrow MSCs on human AML cells differ among patients, the final cytokine-mediated effects of the MSCs during coculture is growth enhancement and inhibition of apoptosis.

CXCL8 derived from mesenchymal stromal cells supports survival and proliferation of acute myeloid leukemia cells through the PI3K/AKT pathway

“…A recent study showed an altered local cytokine secretome of AML blasts and BM‐MSC coculture, with supra‐additive levels (more than the cumulative levels of individually cultured MSCs and AML cells) of CCL3, CCL4, CXCL8, and IL‐6 (15). Consistent with this, CXCL8 mRNA levels were significantly increased in AML BM‐MSCs ( P < 0.01) cocultured with the HL60 ( P < 0.01) and THP1 ( P < 0.01) cell lines compared with the monocultures.…”

“…In addition, BM‐MSCs constitutively release chemokines, such as CXCL12, CXCL8, under the stress of inflammation and hypoxia. Recent studies have shown that BM‐MSC–secreted CXCL8 promotes AML cell growth and metastasis in a paracrine manner, resulting in chemo‐resistance, residual disease, and recurrence (14, 15). We investigated the role of CXCL8 derived from AML BM‐MSCs on the growth of AML cell lines using a direct contact coculture system.…”

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“…In hematological malignancies, BM-MSC from myelodysplastic syndrome (MDS) and AML patients often exhibit altered gene expression profiles, an aberrant Priority Research Paper phenotype, and abnormal functional properties compared to normal donor-derived BM-MSC [5]. Although many studies support these findings [6][7][8], little is known about how genetic aberrations in tumor cells differentially impact the genetic and phenotypic changes in the tumor stroma. In this study, we show specific and common transcriptional changes in BM-MSC driven in vivo by leukemia cells harboring different genotypes.…”

Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia

“…Ferritin is a multi-functional protein regulating several biological processes at both extra and intracellular levels that could be relevant in AML biology including cell proliferation, immunosuppression, angiogenesis, and chemoresistance. Several inflammatory cytokines including interleukin-1β (IL-1β), IL-6, TNF-α, or growth factors such as insulin-like growth factor (IGF-1) responsible for ferritin expression through NF-kB activation are frequently elevated in AML patients and display a crucial role in the LSC niche [31][32][33][34]. It has been shown that inflammatory cytokines could regulate H-ferritin expression at the transcriptional level and both H and L-ferritin at the translational level.…”