Bone marrow mesenchymal stem and progenitor cells in myeloid malignancies

Abstract

Hematopoietic stem cells (HSCs) reside in bone marrow (BM) microenvironment / niche to self-renew and generate all types of mature blood cells in postnatal life. This process is called hematopoiesis. Normal hematopoiesis is tightly regulated by both intrinsic signaling in HSCs and extrinsic signals from BM niche. Despite the involvement of BM niche in normal and malignant hematopoiesis has been reported, how different BM cellular niche contribute to leukemia progression and how leukemia cells affect their BM niche remain largely unknown. The overall aim of this thesis was to determine the roles of BM niche cells in the regulation of different myeloid malignancies, and understand the underlying mechanisms.

In study I, by taking advantage of Sipa1-/- mouse model, we revealed that the loss of Sipa1 in mice led to BM niche alterations before the onset of MDS/MPN, and confirmed that the loss of Sipa1 in BM niche, but not in hematopoietic cells led to the MDS/MPN. Moreover, we detected abnormal inflammatory cytokines and growth factors in the BM stromal cells of the disease-free young adult Sipa1-/- mice, which could contribute to the pathogenesis of the MDS/MPN in aged Sipa1-/- mice. This study provides evidence for BM niche-induced MDS/MPN and the underlying molecular and cellular mechanisms.

Given the distinct pathogenesis of different types of myeloid malignancies, we further investigated the contributions of BM niche to AML progression using MLL-AF9+ AML mouse model in study II. We detected alterations of BM niche cells in symptomatic AML mice, and confirmed similar alterations of BM stromal cells in the NSG mice engrafted with primary patient AML cells. Furthermore, BM niche cells in the AML mice produced altered growth factors, cytokines, and matrix proteins. Dynamic BM niche cell analysis and gene expression assay revealed that the BM niche alterations correlated with AML burden. We next functionally determined the roles of BM MSCs marked by Ebf2 expression in AML progression. We demonstrated that the Ebf2+ cells participated in AML BM niche formation. Notably, the depletion of Ebf2+ cells accelerated AML development in mice, indicating the suppressive roles of native BM niche to AML development. This study indicated that AML cells educated normal BM niche into a reinforcing AML BM niche contributing to AML progression.

In study III, we found that BM MSCs altered their phenotype with reduced SCA1 expression in non-adherent culture, emphasizing culture-related alterations of BM MSC immunophenotype. In study IV, by using LTC-IC assay and single cell PCR, we revealed diverse expressions of leukotriene signaling molecules and minor effects of ALOX5 and CYSLT1 antagonists on CML LSC growth, particularly in the presence of BM stromal cells in vitro.

All together, we phenotypically, molecularly, and functionally characterized leukemic BM niche and determined the niche contributions to different myeloid malignancies. Targeting on BM niche factors or restore BM niche components might be new therapeutic strategies for these myeloid malignancies.