Infliximab therapy together with tyrosine kinase inhibition targets leukemic stem cells in chronic myeloid leukemia

Autor: Till Braunschweig, Fabian Beier, Iris Appelmann, Mirle Schemionek, Oliver Herrmann, Tom Luedde, Steffen Koschmieder, Marlena Bütow, Maja Kim Kuepper, Ivan G. Costa, Tim H. Brümmendorf
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Anti-Inflammatory Agents
Fusion Proteins
bcr-abl
TNF
Tyrosine kinase inhibitor
Apoptosis
Tyrosine-kinase inhibitor
Mice
0302 clinical medicine
Transduction
Genetic
hemic and lymphatic diseases
CML
Myeloid leukemia
Drug Synergism
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Haematopoiesis
Oncology
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Drug Therapy
Combination
Stem cell
Research Article
medicine.drug
medicine.drug_class
Mice
Transgenic
lcsh:RC254-282
Mouse model
03 medical and health sciences
Cell Line
Tumor
Leukemia
Myelogenous
Chronic
BCR-ABL Positive
Genetics
medicine
Animals
Humans
Progenitor cell
Clonogenic assay
Protein Kinase Inhibitors
Cell Proliferation
Leukemic stem cells
Inflammation
Tumor Necrosis Factor-alpha
business.industry
Hematopoietic Stem Cells
Xenograft Model Antitumor Assays
Infliximab
Disease Models
Animal
Pyrimidines
030104 developmental biology
Nilotinib
Drug Resistance
Neoplasm
Cell culture
Cancer research
Therapy
business
Zdroj: BMC Cancer, Vol 19, Iss 1, Pp 1-14 (2019)
BMC cancer 19, 658 (2019). doi:10.1186/s12885-019-5871-2
BMC Cancer
ISSN: 1471-2407
Popis: Background Expression of Bcr-Abl in hematopoietic stem cells is sufficient to cause chronic myeloid leukemia (CML) and tyrosine kinase inhibitors (TKI) induce molecular remission in the majority of CML patients. However, the disease driving stem cell population is not fully targeted by TKI therapy, and leukemic stem cells (LSC) capable of re-inducing the disease can persist. Single-cell RNA-sequencing technology recently identified an enriched inflammatory gene signature with TNFα and TGFβ being activated in TKI persisting quiescent LSC. Here, we studied the effects of human TNFα antibody infliximab (IFX), which has been shown to induce anti-inflammatory effects in mice, combined with TKI treatment on LSC function. Methods We first performed GSEA-pathway analysis using our microarray data of murine LSK cells (lin−; Sca-1+; c-kit+) from the SCLtTA/Bcr-Abl CML transgenic mouse model. Bcr-Abl positive cell lines were generated by retroviral transduction. Clonogenic potential was assessed by CFU (colony forming unit). CML mice were treated with nilotinib or nilotinib plus infliximab, and serial transplantation experiments were performed. Results Likewise to human CML, TNFα signaling was specifically active in murine CML stem cells, and ectopic expression of Bcr-Abl in murine and human progenitor cell lines induced TNFα expression. In vitro exposure to human (IFX) or murine (MP6-XT22) TNFα antibody reduced clonogenic growth of CML cells. Interestingly, TNFα antibody treatment enhanced TKI-induced effects on immature cells in vitro. Additionally, in transplant and serial transplant experiments, using our transgenic CML mouse model, we could subsequently show that IFX therapy boosted TKI-induced effects and further reduced the proportion of malignant stem cells in vivo. Conclusion TNFα signaling is induced in CML stem cells, and anti-inflammatory therapy enhances TKI-induced decline of LSC, confirming that successful targeting of persisting CML stem cells can be enhanced by addressing their malignant microenvironment simultaneously. Electronic supplementary material The online version of this article (10.1186/s12885-019-5871-2) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje