TitleImmortalised chronic myeloid leukemia (CML) derived mesenchymal stromal cells (MSCs) line retains the immunomodulatory and chemoprotective properties of CML patient-derived MSCs.
Publication TypeJournal Article
Year of Publication2024
AuthorsBenjamin ESathya Bam, Vinod E, Illangeswaran RStephen St, Rajamani BM, Vidhyadharan RThalayattu, Bagchi A, Maity A, Mohan A, Parasuraman G, Amirtham SManickam, Abraham A, Velayudhan SR, Balasubramanian P
JournalCell Signal
Volume116
Pagination111067
Date Published2024 Apr
ISSN1873-3913
KeywordsBone Marrow, Gene Expression Profiling, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mesenchymal Stem Cells, Tumor Microenvironment
Abstract

Despite the success of Tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), leukemic stem cells (LSCs) persist, contributing to relapse and resistance. CML Mesenchymal Stromal Cells (MSCs) help in LSC maintenance and protection from TKIs. However, the limited passage and self-differentiation abilities of primary CML MSCs hinder extensive research. To overcome this, we generated and characterized an immortalised CML patient-derived MSC (iCML MSC) line and assessed its role in LSC maintenance. We also compared the immunophenotype and differentiation potential between primary CML MSCs at diagnosis, post-treatment, and with normal bone marrow MSCs. Notably, CML MSCs exhibited enhanced chondrogenic differentiation potential compared to normal MSCs. The iCML MSC line retained the trilineage differentiation potential and was genetically stable, enabling long-term investigations. Functional studies demonstrated that iCML MSCs protected CML CD34 cells from imatinib-induced apoptosis, recapitulating the bone marrow microenvironment-mediated resistance observed in patients. iCML MSC-conditioned media enabled CML CD34 and AML blast cells to proliferate rapidly, with no impact on healthy donor CD34 cells. Gene expression profiling revealed dysregulated genes associated with calcium metabolism in CML CD34 cells cocultured with iCML MSCs, providing insights into potential therapeutic targets. Further, cytokine profiling revealed that the primary CML MSC lines abundantly secreted 25 cytokines involved in immune regulation, supporting the hypothesis that CML MSCs create an immune modulatory microenvironment that promotes growth and protects against TKIs. Our study establishes the utility of iCML MSCs as a valuable model to investigate leukemic-stromal interactions and study candidate genes involved in mediating TKI resistance in CML LSCs.

DOI10.1016/j.cellsig.2024.111067
Alternate JournalCell Signal
PubMed ID38281615