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      Chronic myelogenous leukemia, a still unsolved problem: pitfalls and new therapeutic possibilities

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          Abstract

          Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. At the molecular level, the disorder results from t(9;22)(q34;q11) reciprocal translocation between chromosomes, which leads to the formation of an oncogenic BCR–ABL gene fusion. Instead of progress in the understanding of the molecular etiology of CML and the development of novel therapeutic strategies, clinicians still face many challenges in the effective treatment of patients. In this review, we discuss the pathways of diagnosis and treatment of patients, as well as the problems appearing in the course of disease development. We also briefly refer to several aspects regarding the current knowledge on the molecular basis of CML and new potential therapeutic targets.

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          Most cited references 63

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          European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.

          Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.
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            The molecular biology of chronic myeloid leukemia.

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              JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis.

              The roles of the JAK/STAT, Raf/MEK/ERK and PI3K/Akt signal transduction pathways and the BCR-ABL oncoprotein in leukemogenesis and their importance in the regulation of cell cycle progression and apoptosis are discussed in this review. These pathways have evolved regulatory proteins, which serve to limit their proliferative and antiapoptotic effects. Small molecular weight cell membrane-permeable drugs that target these pathways have been developed for leukemia therapy. One such example is imatinib mesylate, which targets the BCR-ABL kinase as well as a few structurally related kinases. This drug has proven to be effective in the treatment of CML patients. However, leukemic cells have evolved mechanisms to become resistant to this drug. A means to combat drug resistance is to target other prominent signaling components involved in the pathway or to inhibit BCR-ABL by other mechanisms. Treatment of imatinib-resistant leukemia cells with drugs that target Ras (farnysyl transferase inhibitors) or with the protein destabilizer geldanamycin has proven to be a means to inhibit the growth of resistant cells. This review will tie together three important signal transduction pathways involved in the regulation of hematopoietic cell growth and indicate how their expression is dysregulated by the BCR-ABL oncoprotein.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2019
                08 March 2019
                : 13
                : 825-843
                Affiliations
                [1 ]Department of Pharmacology, National Medicines Institute, 00-725 Warsaw, Poland, s.flis@ 123456nil.gov.pl
                [2 ]Department of Hematology, Military Institute of Medicine, 04-141 Warsaw, Poland, tchojnacki@ 123456wim.mil.pl
                Author notes
                Correspondence: Sylwia Flis, Department of Pharmacology, National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland, Tel +48 22 841 0246, Email s.flis@ 123456nil.gov.pl
                Tomasz Chojnacki, Department of Hematology, Military Institute of Medicine, Szaserów 128, 04-141 Warsaw, Poland, Tel +48 26 181 7264, Email tchojnacki@ 123456wim.mil.pl
                Article
                dddt-13-825
                10.2147/DDDT.S191303
                6415732
                © 2019 Flis and Chojnacki. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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