The Yin and Yang of the Bone Marrow Microenvironment: Pros and Cons of Mesenchymal Stromal Cells in Acute Myeloid Leukemia

Abstract

Mesenchymal stromal cells (MSCs) have, for a long time, been recognized as pivotal contributors in the set up and maintenance of the hematopoietic stem cell (HSC) niche, as well as in the development and differentiation of the lympho-hematopoietic system. MSCs also have a unique immunomodulatory capacity, which makes them able to affect, both in vitro and in vivo, the function of immune cells. These features, namely the facilitation of stem cell engraftment and the inhibition of lymphocyte responses, have both proven essential for successful allogeneic stem cell transplantation (allo-SCT), which remains the only curative option for several hematologic malignancies. For example, in steroid-refractory acute graft-vs. host disease developing after allo-SCT, MSCs have produced significant results and are now considered a treatment option. However, more recently, the other side of the MSC coin has been unveiled, because of their emerging role in creating a protective and immune-tolerant microenvironment able to support the survival of leukemic cells and affect the response to therapies. In this light, it has been proposed that the failure of current treatments to efficiently override the stroma-mediated protection of leukemic cells accounts for the high rate of relapse in acute myeloid leukemia, at least in part. In this review, we will focus on emerging microenvironment-driven mechanisms conferring a survival advantage to leukemic cells overt physiological HSCs. This body of evidence increasingly highlights the opportunity to consider tumor-microenvironment interactions when designing new therapeutic strategies.

B-cell lymphoma-2 inhibition and resistance in acute myeloid leukemia

“…Leukemic blasts thrive by exhibiting a higher degree of Bcl-2 when co-cultured with stromal cells. It is therefore possible that eliminating Bcl-2 protein function can eradicate early LSCs[ 40 ].…”

Location First: Targeting Acute Myeloid Leukemia Within Its Niche

“…Beyond adhesion molecules and soluble factors, another mechanism has recently been ascribed to AML-niche interaction. Mitochondrial transfer is a newly described way of communication between BM-derived MSCs and AML cells, which consists of the delivery of fully functional mitochondria from the donor stromal cell to the recipient leukemic cell [128]. Given the novelty of this mechanism, basically two research groups have tried to assess the role of mitochondrial transfer in the AML microenvironment.…”

“…Marlein et al went a little further and provided a detailed description of the process regulating mitochondrial transfer. These authors have suggested that mitochondria uptake by leukemic cells occurs primarily through filamentous actin-based protrusions called tunneling nanotubes (TNTs) [128,131]. TNTs have been described both in cell lines and patient-derived AML cells as structures able to link different cells and to act as a track to carry organelles, such as mitochondria.…”

Bone Marrow-Derived Mesenchymal Stromal Cells: A Novel Target to Optimize Hematopoietic Stem Cell Transplantation Protocols in Hematological Malignancies and Rare Genetic Disorders

“…In addition, MDS-MSCs have been shown to inhibit dendritic cell maturation and alter their functions, including endocytosis, IL-12 secretion, their ability to inhibit T cell proliferation. [115][116][117]. In this light, BM stroma contributes to the creation of a protective and immune-tolerant microenvironment capable of supporting the survival of leukemic cells and affect the response to therapies.…”