NFĸB Targeting in Bone Marrow Mesenchymal Stem Cell-Mediated Support of Age-Linked Hematological Malignancies

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 signi cant increase in MSCs, based on phenotype, for patients with BM brosis. 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 identi ed 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.

Revealing role of epigenetic modifiers and DNA oxidation in cell-autonomous regulation of Cancer stem cells

“…We do not propose to change the standard of care, but to monitor circulating BCCs as a functional indicator for targeted treatment to prolong BC remission. Studies with hematological cancer showed that induced differentiation of leukemia stem cells with bortezomib could induce chemosensitivity [ 61 ]. Despite the limited number of analyzed BCCs in blood (Table 1 ), the evidence showed intriguing information that similar analyses could be used in expanded studies to guide how BC patients are treated.…”

Bone Marrow Niches and Tumour Cells: Lights and Shadows of a Mutual Relationship

“…Indeed, EVs have been studied as cargo of various oligonucleotides of natural and synthetic origin like Paclitaxel, Doxorubicin a nd phytochemicals (64). Another mechanism exploited by MPN-MSCs could be an exaggerated activation of the proinflammatory NF-kB pathway, leading to cytokine release, and proliferation and maintenance of the mutated HSCs and myeloid and lymphoid precursors (65,66).…”

“…Moreover, based on the reported hyperactive NF-kB signalling in MPN-MSCs, this pathway could serve as a target in a combined therapeutic approach against haematological malignancies, using for example a NF-kB inhibitor such as Bortezomib or Carfilzomib (66).…”

POT1a deficiency in mesenchymal niches perturbs B-lymphopoiesis

“…In the age-remodelled BM, MSCs show alteration that reduced production of niche factors that support HSC maintenance, increased adipogenesis and reduced osteogenesis which contribute to a myeloid skewed phenotype of HSCs in aged marrow 17 . Several studies show that microenvironments composed of aged MSCs associate with leukemia development 18 . However, whether cell intrinsic ageing of MSCs affects their function to support normal and pathogenic haematopoiesis, or as a source of tissue regeneration, remains unknown.…”