Normal and leukemic stem cell niche interactions

Abstract

Purpose of review Normal hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) interact with the stem cell niche bone marrow in different ways. Understanding the potentially unique microenvironmental regulation of LSCs is key to understanding in-vivo leukemogenic mechanisms and developing novel antileukemic therapies. Recent findings When leukemic cells are engrafted in the stem cell niche, the cellular nature of the niche – including mesenchymal stromal cells – is reprogramed. Altered mesenchymal cells selectively support leukemic cells and reinforce the pro-leukemic environment. As the niche plays an active role in leukemogenesis, its remodeling may significantly influence the leukemogenic pattern, and cause differences in clinical prognosis. Notably, niche cells could be stimulated to revert to a pronormal/antileukemic state, creating potential for niche-based antileukemic therapy. Summary Bone marrow microenvironments are under dynamic regulation for normal and leukemic cells, and there is bi-directional control of leukemic cells in the niche. Leukemic cells are both protected by stroma and able to reprogram stromal cells to transform the niche to a state, which reinforces leukemogenesis. Because of its dynamic nature, the niche could be converted to an environment with antileukemic properties, making it an attractive target for therapy.

Leukemia-Induced Cellular Senescence and Stemness Alterations in Mesenchymal Stem Cells Are Reversible upon Withdrawal of B-Cell Acute Lymphoblastic Leukemia Cells

“…Although few cells (9%) were positive for γH2AX in the LN-MSC, this quantity was reduced to about 3%, after further co-cultivation for 4 days, suggesting that DDR response was functioning appropriately, a result that is in agreement with a transient ROS production in MSC and with the argument that stem cell populations have efficient mechanisms of repair [ 68 , 69 ]. In fact, the absence of genotoxic stress on MSC poses a lower risk for leukemia progression [ 70 ].…”

“…In fact, in the absence of B-ALL cells, MSC reinitiated normal physiological processes. Strategies to remodel the niche toward a pro-normal/anti-leukemic niche would offer HSC opportunities to counteract the leukemic niche influence [ 70 ]. Alternatively, early therapeutic treatment would ensure that BM-MSC and other stromal cells are less affected by leukemic cell growth, guaranteeing a microenvironment prone to rapid recovery and restitution of HSC functioning.…”

Dual Targeting of Stromal Cell Support and Leukemic Cell Growth by a Peptidic PKC Inhibitor Shows Effectiveness against B-ALL

“…Bone marrow (BM) stromal cells, in particular mesenchymal stem cells (MSC) play a pivotal role in cellular homeostasis within the BM microenvironment not only in physiological but also in pathological conditions [1]. Cross-talk between MSC and leukemic cells has reciprocal functional consequences [2,3], and also in surrounding cells, with overwhelming consequences [4,5]. The relevance of this interaction for the leukemic cells is evidenced by the fact that despite the upregulation of antiapoptotic genes, primary leukemic cells are in general incapable of surviving ex vivo without a cell stromal support, and need to be co-cultured with for example BM-MSC [6,7].…”

In Vitro and In Vivo Modeling of Normal and Leukemic Bone Marrow Niches: Cellular Senescence Contribution to Leukemia Induction and Progression

“…Since Schofield drew up his theory about the existence of a physical hematopoietic niche that drives the hematopoietic stem cell (HSC) fate [1], the possibility of some kind of fostering between niche components and cancer development has been envisaged. The HSC niche is currently described as an intricate and interconnected system composed of a large number of cell types that supply a plethora of biochemical signals essential for the production, regulation and maintenance of blood components [2][3][4]. The cellular composition and properties of the niche varies between endosteal (peripheral), and vascular (medullar) locations in the bone marrow (BM), both differentially controlling HSC functions, i.e., maintaining the HSC and progenitors' pool, preserving quiescence, regulating differentiation and supporting regeneration during homeostasis and stress hematopoiesis [5].…”