Page 39 - 2022_02-Haematologica-web

Hematopoiesis
Reversible switching of leukemic cells to a drug- resistant, stem-like subset via IL-4-mediated cross-talk with mesenchymal stroma
Hae-Ri Lee,1 Ga-Young Lee,1 Eung-Won Kim,1 Hee-Je Kim,2 Min-Ho Lee,3 R. Keith Humphries4,5 and Il-Hoan Oh1
1Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University, Seoul, Republic of Korea; 2Division of Hematology, Department of Internal Medicine, St Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 3Department of Life Science, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, Republic of Korea; 4Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada and 5Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
ABSTRACT
Chemoresistance of leukemic cells has largely been attributed to clonal evolution secondary to accumulating mutations. Here, we show that a subset of leukemic blasts in contact with the mes- enchymal stroma undergo cellular conversion into a distinct cell type that exhibits a stem cell-like phenotype and chemoresistance. These stroma-induced changes occur in a reversible and stochastic manner driven by cross-talk, whereby stromal contact induces interleukin-4 in leukemic cells that in turn targets the mesenchymal stroma to facilitate the development of new subset. This mechanism was dependent on interleukin-4-mediated upregulation of vascular cell adhesion molecule- 1 in mesenchymal stroma, causing tight adherence of leukemic cells to mesenchymal progenitors for generation of new subsets. Together, our study reveals another class of chemoresistance in leukemic blasts via functional evolution through stromal cross-talk, and demonstrates dynamic switching of leukemic cell fates that could cause a non-homol- ogous response to chemotherapy in concert with the patient-specific microenvironment.
Introduction
Acute myeloid leukemia (AML) is a heterogeneous, clonal hematopoietic disorder characterized by excessive proliferation of stem cell-like progenitor cells in the bone marrow (BM). AML has a highly variable prognosis1 and a very high risk of relapse particularly in elderly patients.2
Leukemia progression and relapse are widely viewed to occur via clonal evolution from preleukemic cells to overt leukemia driven by genetic mutations,3 followed by additional mutations leading to treatment-resistant, relapsed clone(s).4 However, in- depth clonal analyses have revealed the persistence of founding clones,4 and func- tional heterogeneity among the developed leukemic clones,5 suggesting that other mechanisms may be involved.
Several studies have highlighted leukemic stem cell (LSC) properties contributing to drug resistance:6 AML patients whose leukemic blast exhibit higher levels of stem cell signatures are at greater risk of relapse and have a poorer prognosis.7,8 However, the specific relationship between stemness and functional heterogeneity of LSC related to drug resistance, remains poorly understood.7,9
There is increasing awareness that the microenvironment, including growth fac- tors, cytokines and niche stromal cells, can provide protection to leukemic cells and thereby contribute to the acquisition of chemoresistance.10,11 For example, leukemic cell subsets surviving chemotherapy were localized to the surface of osteoblasts in the BM.12-15 Subsequently, multiple protective signals from the stroma have been shown to enhance leukemic cell survival through activation of receptor tyrosine
Ferrata Storti Foundation
Haematologica 2022 Volume 107(2):381-392
Correspondence:
IL-HOAN OH
iho@catholic.ac.kr
Received: August 16, 2020. Accepted: December 22, 2020. Pre-published: January 14, 2021.
https://doi.org/10.3324/haematol.2020.269944 ©2022 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2022; 107(2)
381
ARTICLE