Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

Abstract

SummaryBone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup. AML-derived BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, but displayed higher clonogenic potential than healthy donor (HD)-derived BM-MSCs. Although HD- and AML-derived BM-MSCs equally provided chemoprotection to AML cells in vitro, AML-derived BM-MSCs were more immunosuppressive/anti-inflammatory, enhanced suppression of lymphocyte proliferation, and diminished secretion of pro-inflammatory cytokines. Multivariate analysis revealed that the level of interleukin-10 produced by AML-derived BM-MSCs as an independent prognostic factor negatively affected overall survival. Collectively our data show that AML-derived BM-MSCs are not tumor related, but display functional differences contributing to therapy resistance and disease evolution.

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

“…5 Lenalidomide and pomalidomide possess pleiotropic anti-tumor properties including also tumor-controlling immune-modulating effects in other hematological BM malignances such as MDS and MM. 9-11 We therefore set out to assess the anti-leukemia effects of lenalidomide and pomalidomide in AML.…”

“…In AML, the high rate of relapse may in part be a result of the inability of current treatments to effectively overcome the protective influence of the BM niche. 5,46 In fact, it has been recently shown that BM mesenchymal stromal cells (BM-MSCs) derived from diagnostic AML patients are strong immunomodulators and provide similar or even higher chemoprotection of AML cells to cytarabine/idarubicin than normal BM-MSCs. 5 Therefore, new compounds or improved combinatory regimens targeting the interaction between the BM microenvironment and AML leukemic cells are very attractive candidates.…”

“…BM-MSCs were obtained, grown and characterized as extensively described by our group. 5,20 Cultures were maintained in a humidified atmosphere with 5% CO 2 at 37⁰C. The study was IRB-approved by the HCB (HCB/2014/0687) and samples received upon signed informed consent.…”

“…In addition, the BM stroma has been involved in the pathogenesis of a variety of hematologic malignances including AML. 5 The interaction of AML cells with the BM microenvironment in functional niches is a major mechanism underlying leukemia maintenance and therapy resistance. 5,6 Thus, the high rate of mortality/morbidity and chemo-resistance in AML guides the search for new compounds with higher efficiency and lower toxicity.…”

“…In fact, it has recently been shown that BM mesenchymal stromal cells (BM-MSCs) derived from diagnostic AML patients are potent immunomodulators and provide similar chemoprotection of AML cells to cytarabine/idarubicin than normal BM-MSCs. 5 Although IMiDs may have an anti-proliferative effect on leukemic cells, they may likely exert pleiotropic and immunomodulatory effects at the stroma-leukemic cell crosstalk, thus improving standard AML intensive chemotherapy by either potentiating AraC/anthracycline efficacy or reducing BM-MSC-derived chemoresistance.…”