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Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Uppsala Hosp, Sect Hematol, Entrance 50, S-75185 Uppsala, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
St Olavs Hosp, Dept Hematol, Trondheim, Norway; Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway.
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2016 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 50, 95-103 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: The simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation.

METHODS: Samples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib). Samples were analyzed by Mesoscale Discovery, Myriad RBM MAP technology and Olink Proseek.

RESULTS: Multiple plasma proteins were differentially expressed before and after initiation of TKI therapy. Protein patterns demonstrated a possible shift towards Th1-immunity and reduced angiogenic stimuli. Further, some plasma proteins were identified that can be of potential interest to study further for biologic, prognostic or therapeutic significance such as E-selectin, uPAR, growth hormone and carbonic anhydrase IX.

CONCLUSIONS: Plasma proteomics seems feasible and useful in CML patients, both for studying patterns of protein expression and for identifying single proteins differentially expressed before and after treatment. Plasma proteomics may be useful to map disease activity and biological processes. Hence, plasma proteomics can be used to understand drug mechanisms and treatment responses in CML.

Place, publisher, year, edition, pages
2016. Vol. 50, 95-103 p.
Keyword [en]
Proteomics, Chronic myeloid leukemia, Tyrosine kinase inhibitor, Th1, Angiogenesis
National Category
Cancer and Oncology Hematology
Identifiers
URN: urn:nbn:se:uu:diva-310831DOI: 10.1016/j.leukres.2016.09.019ISI: 000388315500015PubMedID: 27710869OAI: oai:DiVA.org:uu-310831DiVA: diva2:1058034
Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2017-08-05Bibliographically approved
In thesis
1. Clinical and Immunological Studies in Chronic Myeloid Leukaemia
Open this publication in new window or tab >>Clinical and Immunological Studies in Chronic Myeloid Leukaemia
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic myeloid leukaemia (CML) is characterised by the constitutively active tyrosine kinase BCR-ABL. Standard treatment with tyrosine kinase inhibitors (TKI) in the chronic phase (CP) of CML conveys excellent long-term prognosis but is associated with side effects and costs. Treatment free remission (TFR) is possible in a proportion of patients discontinuing treatment after obtaining deep treatment responses but it is not fully known how to select the right patients for stopping attempts. Treatment of accelerated phase (AP) and blast crisis (BC) is more complicated and the prognosis more dismal. In this thesis, we have studied factors of importance for outcome in CML patients with focus on immunological factors and clinical management.

In a cohort of 32 newly diagnosed CP-CML patients, evidence of active immune escape mechanisms were found. These declined with the course of TKI treatment and at the same time, effector lymphocyte responses were elicited. These anti-leukaemia immune responses might help in the long-term control of CML. Multiple plasma protein markers were also measured with three multiplex platforms in a smaller cohort of patients (n=14). Inflammatory cytokines and other plasma proteins were affected by TKI treatment and multiplexing seems useful for finding potential biomarkers with biologic or prognostic significance in CML.

Patients progressing to AP/BC were studied in a population-based material from the Swedish CML register. Approximately 4% of TKI-treated CP-CML patients transformed to AP/BC within 2 years of diagnosis. Monitoring of treatment responses was suboptimal in 1/3 of these patients and the median survival was 1.4 years after diagnosis of AP/BC. Thus, minimising the risk of disease progression through strict adherence to guidelines for monitoring and treatment is essential.

In a cohort of patients (n=50) discontinuing TKI treatment within a large European trial, musculoskeletal pain was reported by 30% of patients, starting within 1- 6 weeks of TKI discontinuation and spontaneously resolving over time in most cases. Patients (n=56) were also evaluated with a multiplex platform with a total of 162 inflammation- and cancer-related plasma proteins. No predictive protein biomarkers for successful TKI discontinuation could be found. However, profound effects of TKI-treatment were seen and plasma proteomics could be useful for understanding effects of long-term TKI-treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1347
Keyword
chronic myeloid leukaemia, accelerated phase, blast crisis, tyrosine kinase inhibitor, immunology, myeloid-derived suppressor cells, cytokines, proteomics, TKI discontinuation, population-based
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-324272 (URN)978-91-513-0021-4 (ISBN)
Public defence
2017-09-22, Enghoffsalen, Akademiska sjukhuset, Ingång 50, bv, Uppsala, 09:00 (English)
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Available from: 2017-09-01 Created: 2017-08-05 Last updated: 2017-09-08

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Söderlund, StinaChristiansson, LisaPersson, IngerSimonsson, BengtOlsson-Strömberg, UllaLoskog, Angelica
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