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

Abstract

An understanding of the cell interactions occurring in the leukemic microenvironment and their functional consequences for the different cell players has therapeutic relevance. By co-culturing mesenchymal stem cells (MSC) with the REH acute lymphocytic leukemia (ALL) cell line, we have established an in vitro leukemic niche for the functional evaluation of hematopoietic stem/progenitor cells (HSPC, CD34+ cells). We showed that the normal homeostatic control exerted by the MSC over the HSPC is considerably lost in this leukemic microenvironment: HSPC increased their proliferation rate and adhesion to MSC. The adhesion molecules CD54 and CD44 were consequently upregulated in HSPC from the leukemic niche. Consequently, with this adhesive phenotype, HSPC showed less Stromal derived factor-1 (SDF-1)-directed migration. Interestingly, multipotency was severely affected with an important reduction in the absolute count and the percentage of primitive progenitor colonies. It was possible to simulate most of these HSPC alterations by incubation of MSC with a REH-conditioned medium, suggesting that REH soluble factors and their effect on MSC are important for the observed changes. Of note, these HSPC alterations were reproduced when primary leukemic cells from an ALL type B (ALL-B) patient were used to set up the leukemic niche. These results suggest that a general response is induced in the leukemic niche to the detriment of HSPC function and in favor of leukemic cell support. This in vitro leukemic niche could be a valuable tool for the understanding of the molecular events responsible for HSPC functional failure and a useful scenario for therapeutic evaluation.

The bone marrow microenvironment of pre-B acute lymphoblastic leukemia at single-cell resolution

“…MDP were the most communicative during disease progression with changes across many GO-BP for both ligands and receptors. Overall, our results support the notion that the leukemia BMM can alter the activities of HSPCs 36 .…”

Acute Leukemia Induces Senescence and Impaired Osteogenic Differentiation in Mesenchymal Stem Cells Endowing Leukemic Cells with Functional Advantages

“…We have recently established an in vitro leukemic niche (LN) model to simulate BM cell interactions and to study functional alterations of HSC in a leukemic microenvironment [14, 24]. In the present work, we found that leukemic cells induce MSC senescence by a p53-mediated pathway and ROS production.…”

“…Many studies have shown that during leukemia proliferation, the hematopoietic niche is remodeled, altering its properties by mechanisms that are only partially understood, but may include abnormal expression of cell adhesion molecules, aberrant migration capacity, and secretion of soluble factors, among others [9–12]. It is believed that these changes improve the survival and proliferation of leukemic cells in the niche [13] to the detriment of HSC [10, 14]. Specifically, the information related to MSC alterations in the leukemic microenvironment, and the molecular mechanisms involved, is scarce with some exceptions in AML and CML [15–18].…”

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].…”