Abstract
Mesenchymal stem cells (MSCs) can become dysfunctional in patients with hematological disorders. An unanswered question is whether age-linked disruption of the bone marrow (BM) microenvironment is secondary to hematological dysfunction or vice versa. We therefore studied MSC function in patients with different hematological disorders and found decreased MHC-II except from one sample with acute myeloid leukemia (AML). The patients' MSCs were able to exert veto properties except for AML MSCs. While the expression of MHC-II appeared to be irrelevant to the immune licensing of MSCs, AML MSCs lost their ability to differentiate upon contact and rather, continued to proliferate, forming foci-like structures. We performed a retrospective study that indicated a significant increase in MSCs, based on phenotype, for patients with BM fibrosis. This suggests a role for MSCs in patients transitioning to leukemia. NFĸB was important to MSC function and was shown to be a potential target to sensitize leukemic CD34+/CD38- cells to azacitidine. This correlated with their lack of allogeneic stimulation. This study identified NFĸB as a potential target for combination therapy to treat leukemia stem cells and showed that understanding MSC biology and immune response could be key in determining how the aging BM might support leukemia. More importantly, we show how MSCs might be involved in transitioning the high risk patient with hematological disorder to AML.
Highlights
Mesenchymal Stem Cells (MSCs), referred as bone marrow (BM) stromal cells, are found in adult and fetal tissues [1,2,3]
MHC-II was not detected on MSCs from Polycythemia Vera (PV), myelodysplastic syndrome (MDS) and Chronic Myeloid Leukemia (CML) BM whereas the two acute myeloid leukemia (AML) samples showed different MHC-II
This study addressed an early time point that could be important in preventing age-linked hematological disorders transitioning to leukemia
Summary
Mesenchymal Stem Cells (MSCs), referred as bone marrow (BM) stromal cells, are found in adult and fetal tissues [1,2,3]. In BM, MSCs can be located at different anatomical sites - central sinus, trabeculae, endosteal region and compact bone [5, 6]. These locations are sites of hematopoietic activity in which the function of hematopoietic stem cells (HSCs) are supported with MSCs and their differentiated cells [7]. The latter include fibroblasts, adipocytes and osteoblasts [8]. The functional relationship between MSCs and hematopoietic activity are part of the process to maintain BM homeostasis
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