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

Natalia-Del Pilar Vanegas,Paola Fernanda Ruiz-Aparicio,Gloria Inés Uribe,Jean-Paul Vernot,Adriana Linares-Ballesteros

doi:10.3390/ijms22158166

Abstract

Leukemic cell growth in the bone marrow (BM) induces a very stressful condition. Mesenchymal stem cells (MSC), a key component of this BM niche, are affected in several ways with unfavorable consequences on hematopoietic stem cells favoring leukemic cells. These alterations in MSC during B-cell acute lymphoblastic leukemia (B-ALL) have not been fully studied. In this work, we have compared the modifications that occur in an in vitro leukemic niche (LN) with those observed in MSC isolated from B-ALL patients. MSC in this LN niche showed features of a senescence process, i.e., altered morphology, increased senescence-associated β-Galactosidase (SA-βGAL) activity, and upregulation of p53 and p21 (without p16 expression), cell-cycle arrest, reduced clonogenicity, and some moderated changes in stemness properties. Importantly, almost all of these features were found in MSC isolated from B-ALL patients. These alterations rendered B-ALL cells susceptible to the chemotherapeutic agent dexamethasone. The senescent process seems to be transient since when leukemic cells are removed, normal MSC morphology is re-established, SA-βGAL expression is diminished, and MSC are capable of re-entering cell cycle. In addition, few cells showed low γH2AX phosphorylation that was reduced to basal levels upon cultivation. The reversibility of the senescent process in MSC must impinge important biological and clinical significance depending on cell interactions in the bone marrow at different stages of disease progression in B-ALL.

Highlights

Diverse and complex cues from the bone marrow (BM) microenvironment are essential to achieve a functional hematopoietic stem cell (HSC) and hematopoiesis [1,2,3]
The BM niche is the main site of relapse in pediatric B-cell acute lymphoblastic leukemia (B-ALL) [10], suggesting that privileged niches are formed in this location to support leukemic cell growth [11]
In an in vitro leukemic niche (LN) model [26], we have recently shown that B-ALL cell lines induced in mesenchymal stem cells (MSC) a significant increase in senescence-associated β-galactosidase (SA-βGAL) activity together with an augmented p53 gene expression and cytoplasmic reactive oxygen species (ROS) production, and a subsequent cell cycle arrest [27]

Summary

Introduction

Diverse and complex cues from the bone marrow (BM) microenvironment are essential to achieve a functional hematopoietic stem cell (HSC) and hematopoiesis [1,2,3]. Leukemic cells growing in the BM induce a very stressful condition and important alterations in the BM microenvironment, affecting the composition, organization, and physiology of the different cell populations [4,5,6,7]. These modifications include the elaboration of an evolving BM supportive niche for leukemic cells that would be responsible for the development of chemotherapy resistance and disease relapse [8,9]. Chemokines, and growth factors, and other soluble components are responsible for the observed effect in this two-way interaction [21,22]

Methods

Results

Conclusion