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.
Highlights
Acute myeloid leukemia (AML) is an aggressive malignancy that mainly affects the elderly; the disease is characterized by bone marrow infiltration of immature leukemic blasts [1], and it is highly heterogeneous with respect to leukemia cell biology as well as response to therapy [2]
Our studies suggest that mesenchymal stem cell (MSC)-derived cytokines have antiapoptotic effects and support AML cell proliferation for most patients, but the molecular mechanisms causing these effects differ among patients
AML cell proliferation was significantly increased by coculture with MSCs compared with the corresponding control cultures with AML cells alone (Figure 1A); this increase reached statistical significance for all three MSC donors (p ≤ 0.001, Wilcoxon’s signed-rank test), even though the AML cells showed undetectable proliferation for two patients, both when cultured in medium alone and in the presence of all three MSC donor cells
Summary
Acute myeloid leukemia (AML) is an aggressive malignancy that mainly affects the elderly; the disease is characterized by bone marrow infiltration of immature leukemic blasts [1], and it is highly heterogeneous with respect to leukemia cell biology as well as response to therapy [2]. Mesenchymal stem or stromal cells (MSCs) are capable of self-renewal and differentiation into osteoblasts, chondrocytes, or adipocytes [5], the most immature MSCs can transdifferentiate into other embryonic lineages [6, 7]. The cells can be isolated from almost any kind of connective tissue [8, 9], and bone marrow MSCs provide a microenvironment for growth, differentiation, and survival of both normal [10] and leukemic [11] hematopoietic cells. The bone marrow MSC population seems to be important in leukemogenesis [12] and to contribute to chemoresistance through its release of specific soluble mediators [13, 14]
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