Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow

Abstract

Degeneration of normal hematopoietic cells is a shared feature of malignant diseases in the hematopoietic system. Previous studies have shown the exhaustion of hematopoietic progenitor cells (HPCs) in leukemic marrow, whereas hematopoietic stem cells (HSCs) remain functional upon relocation to non-leukemic marrow. However, the underlying cellular mechanisms, especially the specific niche components that are responsible for the degeneration of HPCs, are unknown. In this study, we focused on murine bone mesenchymal stem cells (MSCs) and their supporting function for normal hematopoietic cells in Notch1-induced acute T-cell lymphocytic leukemia (T-ALL) mice. We demonstrate that the proliferative capability and differentiation potential of T-ALL MSCs were impaired due to accelerated cellular senescence. RNA-seq analysis revealed significant transcriptional alterations in leukemic MSCs. After co-cultured with the MSCs from T-ALL mice, a specific inhibitory effect on HPCs was defined, whereas in vivo repopulating potential of normal HSCs was not compromised. Furthermore, osteoprotegerin was identified as a cytokine to improve the function of T-ALL MSCs and to enhance normal HPC output via the p38/ERK pathway. Therefore, this study reveals a novel cellular mechanism underlying the inhibition of HPC generation in T-ALL. Leukemic MSCs may serve as a cellular target for improving normal hematopoietic regeneration therapeutically.

Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment

“…More recently, CML and ALL mouse models have shown that a reduction in SDF-1 levels in BM is responsible for impaired LT-HSC or human CD34+ homing and retention [17,18,19,20]. This apparently modest change in cytokine production by stromal cells has profound effects on HSC biology.…”

“…Reduced SDF-1 secretion, essential chemokine for HSC homing and retention, and an increase of other chemokines and cytokines by BM stromal cells are responsible for impaired support for HSC and a selective growth advantage for leukemic cells [17,18,19]. Leukemic cells induced an SCF-dependent CD34+ progenitors’ displacement to novel malignant microenvironments [20].…”

Pro-inflammatory-Related Loss of CXCL12 Niche Promotes Acute Lymphoblastic Leukemic Progression at the Expense of Normal Lymphopoiesis

“…However, it is becoming clear that progressive changes in both, cell composition and function of the microenvironment may govern abnormal progenitor cell activity and drive to establishment of exclusive structures suitable for leukemic cell proliferation but incompatible for sustaining normal hematopoiesis, that ultimately lead to disease (4, 22–26). Previous studies in mice models and leukemia patients revealed that some of the BM microenvironmental alterations include an increased concentration of SCF and a decreased production of CXCL12 (2, 24, 27).…”

The functional interplay between systemic cancer and the hematopoietic stem cell niche

“…In a Notch-induced T cell ALL model, bone marrow-derived MSCs isolated from T cell ALL-bearing mice have decreased expression of hematopoietic stem and progenitor cell (HSPC) niche-associated genes and impaired functionality of Lineage − Sca-1 + cKit + (LSK) stem cells after short term co-culture (Lim, et al, 2016). More specifically, there are examples of changes in bone marrow stromal cells in the osteoblastic, neural, and endothelial compartments.…”