Studies of Some Mechanisms of Drug Resistance in Chronic Myeloid Leukemia (CML)

Turkina, Anna; Logacheva, Natalia P.; Stromskaya, T. P.; Заботина, Т. Н.; Kuznetzov, S; Sachibzadaeva, Kuralay K.; Tagiev, A. F.; Juravlev, Vacheslav S.; Хорошко, Н. Д.; Baryshnikov, A. Yu.; Stavrovskaya, A. A.

doi:10.1007/978-1-4615-4811-9_52

Cited by 17 publications

(9 citation statements)

References 14 publications

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“…This is discrete from acquired TKI resistance because of BCRABL point mutation or duplication. 39 We explored the hypothesis that Fas resistance contributes to intrinsic CML LSC TKI insensitivity. The corollary to this hypothesis is that blocking Fap1 delays TKI resistance and prevents relapse after treatment discontinuation.…”

Section: Discussionmentioning

confidence: 99%

The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia

et al. 2016

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Chronic myeloid leukemia (CML) is characterized by expression of Bcr-abl, a tyrosine kinase oncogene. Clinical outcomes in CML were revolutionized by development of Bcr-abl-targeted tyrosine kinase inhibitors (TKIs), but CML is not cured by these agents. CML leukemia stem cells (LSCs) are relatively TKI insensitive and persist even in remission. LSC persistence results in relapse upon TKI discontinuation, or drug resistance or blast crisis (BC) during prolonged treatment. We hypothesize that increased expression of Fas-associated phosphatase 1 (Fap1) in CML contributes to LSC persistence and BC. As Fap1 substrates include Fas and glycogen synthase kinase-3β (Gsk3β), increased Fap1 activity in CML is anticipated to induce Fas resistance and stabilization of β-catenin protein. Resistance to Fas-induced apoptosis may contribute to CML LSC persistence, and β-catenin activity increases during BC. In the current study, we directly tested the role of Fap1 in CML LSC persistence using in an in vivo murine model. In TKI-treated mice, we found that inhibiting Fap1, using a tripeptide or small molecule, prevented TKI resistance, BC and relapse after TKI discontinuation; all events observed with TKI alone. In addition, Fap1 inhibition increased Fas sensitivity and decreased β-catenin activity in CD34+ bone marrow cells from human subjects with CML. Therapeutic Fap1 inhibition may permit TKI discontinuation and delay in progression in CML.

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Section: Discussionmentioning

confidence: 99%

The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia

et al. 2016

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“…CML cells are recognized as being relatively resistant to Fas-induced apoptosis, but mechanisms for this were not well defined. Fas expression is not consistently decreased in CML, and expression of FasL in CML bone marrow actually increases with progressive disease [29,30]. Since Fas resistance worsens with drug resistance and BC, the latter is thought to be an unsuccessful attempt at compensation [31].…”

Section: Discussionmentioning

confidence: 99%

Fas-associated phosphatase 1 mediates Fas resistance in myeloid progenitor cells expressing the Bcr–abl oncogene

Huang

Bei

Eklund

2012

Leukemia & Lymphoma

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The interferon consensus sequence binding protein (Icsbp) is a transcription factor that influences multiple aspects of myelopoiesis. Expression of Icsbp is decreased in the bone marrow of human subjects with chronic myeloid leukemia (CML), and studies in murine models suggest that Icsbp functions as an anti-oncogene for CML. We previously identified a set of Icsbp target genes that may contribute to this anti-oncogene effect. The set includes PTPN13, the gene encoding Fas-associated phosphatase 1 (Fap1, a Fas antagonist). We previously demonstrated that myeloid progenitor cells from Icsbp-knockout mice exhibit Fap1-dependent Fas resistance. In the present study, we determined that the Fas resistance of Bcr−abl+ cells is Icsbp- and Fap1-dependent. We also found that treatment of Bcr−abl+ bone marrow cells with a Fap1-blocking peptide prevents in vitro selection of a tyrosine kinase inhibitor (TKI)-resistant population. Therefore, these results have implications for therapeutic targeting of the Fas-resistant leukemia stem cell population and addressing TKI resistance in CML.

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“…The majority of published data suggest that ABCB1 expression is unlikely to be significantly correlated with prognosis and clinical outcome [162,163,170,171]. However, the results of the other studies in the CML patients suggest that ABCB1 expression may be regarded as an unfavorable prognostic factor in the blastic phase CML [125,164,[172][173][174][175] or CR for the chronic phase CML [176]. The significance of ABCB1 expression for chemotherapy outcome of different CML stages is still unclear.…”

Section: Abc Transporters In Hematological Malignanciesmentioning

confidence: 95%

Revisiting the ABCs of Multidrug Resistance in Cancer Chemotherapy

Tiwari

Sodani²,

Dai³

et al. 2011

CPB

200

147

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The adenosine tri-phosphate binding cassette (ABC) transporters are one of the largest transmembrane gene families in humans. The ABC transporters are present in a number of tissues, providing protection against xenobiotics and certain endogenous molecules. Unfortunately, their presence produces suboptimal chemotherapeutic outcomes in cancer patient tumor cells. It is well established that they actively efflux antineoplastic agents from cancer cells, producing the multidrug resistance (MDR) phenotype. The inadequate response to chemotherapy and subsequent poor prognosis in cancer patients can be in part the result of the clinical overexpression of ABC transporters. In fact, one of the targeted approaches for overcoming MDR in cancer cells is that directed towards blocking or inhibiting ABC transporters. Indeed, for almost three decades, research has been conducted to overcome MDR through pharmacological inhibition of ABC transporters with limited clinical success. Therefore, contemporary strategies to identify or to synthesize selective "resensitizers" of ABC transporters with limited nonspecific toxicity have been undertaken. Innovative approaches en route to understanding specific biochemical role of ABC transporters in MDR and tumorigenesis will prove essential to direct our knowledge towards more effective targeted therapies. This review briefly discusses the current knowledge regarding the clinical involvement of ABC transporters in MDR to antineoplastic drugs and highlights approaches undertaken so far to overcome ABC transporter-mediated MDR in cancer.

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Studies of Some Mechanisms of Drug Resistance in Chronic Myeloid Leukemia (CML)

Cited by 17 publications

References 14 publications

The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia

The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia

Fas-associated phosphatase 1 mediates Fas resistance in myeloid progenitor cells expressing the Bcr–abl oncogene

Revisiting the ABCs of Multidrug Resistance in Cancer Chemotherapy

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