Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option

Abstract

Although tyrosine kinase inhibitors are effective for treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be due to bone marrow (BM) niche protection. However, little is known about the underlying mechanisms. We here molecularly and functionally characterized BM niches in CML patients at diagnosis and revealed the altered niche composition and function in the CML patients. Long-term culture initiating cell (LTC-IC) assay showed that the mesenchymal stem cells from CML patients displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in CML patient BM cellular niches. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.

The functional and molecular impact of triamcinolone acetonide on primary human bone marrow mesenchymal stem cells

“…CFU-F assessing MSC self-renewal and their functionality was performed as described 17 , 18 . Briefly, the cells were first exposed to complete DMEM or complete DMEM + 10 nM TA for 24 h. After washing, cells were seeded at 200 cells/well in a 6 -well plastic plate and cultured under hypoxic conditions (1% O 2 ) for 10–12 days, fixed in methanol and stained with Giemsa (Sigma-Aaldrich, Darmstadt, Germany) for CFU-F colony counting.…”

“…After 24 h incubation of BM MSCs at passage 1–5 with or without 10 nM TA under hypoxic conditions, cells were dissociated and collected for the respective differentiation assay, as previously described 17 .…”

The Chemokine CXCL14 as a Potential Immunotherapeutic Agent for Cancer Therapy

“…Dolinska et al have shown that CXCL14 expression is absent in bone marrow niche cells of chronic myeloid leukemia patients. However, with CXCL14 restoration, leukemia-initiating stem cells were suppressed, and their sensitivity to imatinib treatment was enhanced [ 42 , 43 ]. Parikh et al have revealed that CXCL14 expression inhibits tumor growth and increases tumor-infiltrating lymphocytes in HPV-negative squamous-cell carcinoma of the oral cavity [ 44 ].…”

“…Based on the antitumor activity of CXCL14 through immune activation in several cancers [ 32 , 40 , 42 , 43 , 45 , 65 , 66 ], we propose that CXCL14 could be used in cancer immunotherapy, particularly in treating HPV+ cancers [ 40 , 42 ]. This possibility is further supported by the association of high CXCL14 expression with better patient survival in multiple cancers, including HNSCC and CxCa [ 41 ].…”

High-throughput formulation of reproducible 3D cancer microenvironments for drug testing in myelogenous leukemia

“…As a result -via enhancing the metabolic plasticity, pro-survival signaling and proliferation of leukemic cells -the bone marrow cells may favor the persistence and progression of leukemia, including the self-renewal capacities of the malignant progenitor cells (Vianello et al, 2010). Overall, the bone marrow microenvironment is known to contribute to myeloid malignancies and protect CML cells from drug-induced cytotoxicity through various routes of intercellular communication (Chen et al, 2021;Dolinska et al, 2023;Joshi et al, 2021;Kolba et al, 2019;Korn and Méndez-Ferrer, 2017;Le et al, 2020;Pal et al, 2022;Patterson and Copland, 2023). For example, immunosuppression and T-cell exhaustion (Swatler et al, 2022b(Swatler et al, , 2022a are promoted in the presence of leukemic extracellular vesicles (EVs).…”