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Monitoring tyrosine kinase inhibitor therapeutic responses with a panel of metabolic biomarkers in chronic myeloid leukemia patients.

ABSTRACT: The aim of this study is to investigate the potential biomarkers associated with chronic myeloid leukemia (CML), reveal the metabolite changes related to the continuous phases of tyrosine kinase inhibitors (TKIs), and find the potential biomarkers associated with treatment effects. Fifty-two patients with CML and 26 matched healthy people were enrolled as the discovery set. Another 194 randomly selected CML patients treated with TKI were chosen as the external validation set. Plasma samples from the patients and controls were profiled using the gas chromatography-mass spectrometry-based metabonomic approach. Multivariate and univariate statistical analyses were combined to select the differential metabolic features. The gas chromatography-mass spectrometry-based metabolomics showed a clear clustering and separation of metabolic patterns from healthy controls and pre- and post-TKI treatment CML patients in the discovery set. We identified 9 metabolites that differentiated CML patients from healthy controls, including lactic acid, isoleucine, glycerol, glycine, myristic acid, d-sorbitol, d-galactose, d-glucose, and myo-inositol. Among the 9 markers, glycerol and myristic acid had the most significant association with TKI treatment effects in both discovery and external validation sets. In the receiver operating characteristic analysis, the combination of glycerol and myristic acid showed a better discrimination performance compared to a single biomarker. The results indicated that metabolic profiling has the potential for diagnosis of CML and the panel of biomarkers including myristic acid and glycerol could be useful in monitoring TKI therapeutic responses.

SUBMITTER: Yang B

PROVIDER: S-EPMC5834806 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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Monitoring tyrosine kinase inhibitor therapeutic responses with a panel of metabolic biomarkers in chronic myeloid leukemia patients.

Yang Bingyu B Wang Chang C Xie Yiyu Y Xu Liangjing L Wu Xiaojin X Wu Depei D

Cancer science 20180214 3

The aim of this study is to investigate the potential biomarkers associated with chronic myeloid leukemia (CML), reveal the metabolite changes related to the continuous phases of tyrosine kinase inhibitors (TKIs), and find the potential biomarkers associated with treatment effects. Fifty-two patients with CML and 26 matched healthy people were enrolled as the discovery set. Another 194 randomly selected CML patients treated with TKI were chosen as the external validation set. Plasma samples from ...[more]

PMID: 29316075

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Project description:Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib, are effective forms of therapy for various types of solid cancers and Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia. A number of TKIs have been known to have strong effects on T cells, particularly cluster of differentiation (CD) 4+CD25+ T cells, also known as regulatory T cells (Tregs). There is currently a deficit in the available clinical data regarding this area of study. In the present study, a total of 108 peripheral blood samples were collected from patients with chronic myeloid leukemia (CML) at diagnosis (n=31), and at 3 and 6 months following treatment with TKI [imatinib (n=12), dasatinib (n=11) and nilotinib groups (n=8)] and healthy controls (n=15). Peripheral blood mononuclear cells were collected from the patients prior to and following TKI treatment. The subtype and number of T lymphocytes in patients and healthy donors were analyzed using flow cytometry. Additionally, flow cytometry and ELISA were used to detect the proliferation and suppression of Tregs. Expression of cytokines and other molecules [forkhead box P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor (GITR) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)] were also analyzed at 3 and 6 months following treatment with TKIs. It was indicated that, at diagnosis, a similar number of lymphocytes were detected in patients and control. However, following treatment with a TKI, the number of total T cells, Tregs, CD4+ T and CD8+ T cells decreased to various degrees in patients. Furthermore, the decrease in the number of Tregs was more significant with time. Although treatment with imatinib, dasatinib and nilotinib demonstrated similar inhibitory effects on the quantity of Tregs in vivo, the TKIs exhibited differential effects on the function of Tregs in vitro. Proliferation, suppression and expression of cytokines [interleukin (IL)-4, IL-10 and transforming growth factor (TGF)-β] and molecules (FOXP3, GITR and CTLA-4) decreased significantly in treatment groups with imatinib and dasatinib. The decrease was not significant in the nilotinib treatment group. Imatinib and dasatinib may exert more marked inhibitory roles compared with nilotinib on regulating the number and function of Tregs. These results suggest that personalized treatment and follow-up of CML patients during TKI treatment, particularly for those who received post-transplant TKI treatment may be beneficial.

Project description:Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR-ABL and by crossing BCR-ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR-ABL and NUP98-HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR-ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38-CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells.

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Monitoring tyrosine kinase inhibitor therapeutic responses with a panel of metabolic biomarkers in chronic myeloid leukemia patients.

Publications

Monitoring tyrosine kinase inhibitor therapeutic responses with a panel of metabolic biomarkers in chronic myeloid leukemia patients.

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