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https://www.readbyqxmd.com/read/29222245/novel-approaches-to-therapy-in-cml
#1
REVIEW
Ravi Bhatia
Treatment with tyrosine kinase inhibitors (TKIs) results in remission and prolongation of survival in most chronic myeloid leukemia (CML) patients but fails to eliminate the leukemia stem cells (LSCs) responsible for disease development and propagation. This accounts for the clinical observation that TKI discontinuation leads to rapid leukemia relapse. Most patients require continued treatment to prevent relapse, with associated risk of relapse, toxicity, teratogenic effects, financial burden, and noncompliance...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29205725/pleckstrin-homology-domain-of-p210-bcr-abl-interacts-with-cardiolipin-to-regulate-its-mitochondrial-translocation-and-subsequent-mitophagy
#2
Kentaro Shimasaki, Miho Watanabe-Takahashi, Masato Umeda, Satoru Funamoto, Yoshiro Saito, Noriko Noguchi, Keigo Kumagai, Kentaro Hanada, Fujiko Tsukahara, Yoshiro Maru, Norihito Shibata, Mikihiko Naito, Kiyotaka Nishikawa
Chronic myeloid leukemia (CML) is caused by the chimeric protein p210 BCR-ABL encoded by a gene on the Philadelphia chromosome. Although the kinase domain of p210 BCR-ABL is an active driver of CML, the pathological role of its pleckstrin homology (PH) domain remains unclear. Here, we carried out phospholipid vesicle-binding assays to show that cardiolipin (CL), a characteristic mitochondrial phospholipid, is a unique ligand of the PH domain. Arg726, a basic amino acid in the ligand-binding region, was crucial for ligand recognition...
December 5, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/29205121/synthesis-and-structure-activity-relationship-exploration-of-some-potent-anti-cancer-phenyl-amidrazone-derivatives
#3
Almeqdad Y Habashneh, Mustafa M El-Abadelah, Sanaa K Bardaweel, Mutasem O Taha
BACKGROUND: Amidrazones have been reported to have significant anti-tumor properties against several cancer cell lines. OBJECTIVES: The current project aims to profile the structure-anticancer activity relationship of phenyl-amidrazons. METHODS: Fifteen phenyl-amidrazone-piperazine derivatives were prepared and tested against four cancer cell lines (leukemia, prostate, breast and colon cancers). RESULTS: Six compounds illustrated low micromolar anticancer IC50 values, while the remaining compounds were either inactive or of moderate potencies...
December 4, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/29200684/the-role-of-mutation-testing-in-patients-with-chronic-myeloid-leukemia-in-chronic-phase-after-imatinib-failure-and-their-outcomes-after-treatment-modification-single-institutional-experience-over-13-years
#4
Puligundla Krishna Chaitanya, Karnam Ashok Kumar, Bala Stalin, Gundeti Sadashivudu, Maddali Lakshmi Srinivas
Introduction: BCR-ABL1 kinase domain mutations represent the most frequent mechanism of resistance to tyrosine kinase inhibitor (TKI) therapy, being detected in 40%-50% of imatinib-resistant patients with chronic myeloid leukemia in chronic phase (CML-CP). Over 100 BCR-ABL1 single-point mutations have been reported in patients with imatinib-resistant CML. There were few studies reported from India on BCR-ABL kinase mutations in imatinib failure patients. We present our data on imatinib resistance mutation analysis (IRMA) and use of imatinib dose hike and 2nd-generation TKI at our institute...
July 2017: Indian Journal of Medical and Paediatric Oncology
https://www.readbyqxmd.com/read/29199506/inadequate-response-to-imatinib-treatment-in-chronic-myeloid-leukemia-due-to-a-drug-interaction-with-phenytoin
#5
S Osorio, V Escudero-Vilaplana, I Gómez-Centurión, E González-Arias, X García-González, J L Díez
Imatinib mesylate and the newer BCR-ABL tyrosine kinase inhibitors are the standard therapy for chronic myeloid leukemia. Although these are remarkably effective drugs, some mechanisms of resistance have been identified including drug-to-drug interactions. Here we present the case of a chronic myeloid leukemia patient with an inadequate response to imatinib due to concurrent phenytoin administration. Conspicuously low imatinib plasma trough levels were documented. Imatinib dose was increased from 400 to 800 mg with good response...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29192326/eps8-regulates-proliferation-apoptosis-and-chemosensitivity-in-bcr-abl-positive-cells-via-the-bcr-abl-pi3k-akt-mtor-pathway
#6
Rui Huang, Huimin Liu, Yiran Chen, Yanjie He, Qian Kang, Sanfang Tu, Yingzhi He, Xuan Zhou, Lei Wang, Jilong Yang, Anqin Wu, Yuhua Li
Although the introduction of tyrosine kinase inhibitors greatly improved the survival of patients with chronic myeloid leukemia (CML), drug resistance remains a problem. Thus, mechanism-based novel therapeutic targets warrant exploration. Recently, epidermal growth factor receptor kinase substrate 8 (EPS8), which has been identified as an oncogene and plays an important role in a broad spectrum of solid tumours, was reported to be related to poor prognosis or chemoresistance in acute leukemia patients. However, its role in CML remains unclear...
January 2018: Oncology Reports
https://www.readbyqxmd.com/read/29190894/microrna-212-abcg2-axis-contributes-to-development-of-imatinib-resistance-in-leukemic-cells
#7
Meike Kaehler, Johanna Ruemenapp, Daniel Gonnermann, Inga Nagel, Oliver Bruhn, Sierk Haenisch, Ole Ammerpohl, Daniela Wesch, Ingolf Cascorbi, Henrike Bruckmueller
BCR-ABL-independent resistance against tyrosine kinase inhibitor is an emerging problem in therapy of chronic myeloid leukemia. Such drug resistance can be linked to dysregulation of ATP-binding cassette (ABC)-transporters leading to increased tyrosine kinase inhibitor efflux, potentially caused by changes in microRNA expression or DNA-methylation. In an in vitro-imatinib-resistance model using K-562 cells, microRNA-212 was found to be dysregulated and inversely correlated to ABC-transporter ABCG2 expression, targeting its 3'-UTR...
November 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29187870/ectopic-expression-of-snail-and-twist-in-ph-leukemia-cells-upregulates-cd44-expression-and-alters-their-differentiation-potential
#8
Noa Kidan, Hazem Khamaisie, Nili Ruimi, Shay Roitman, Elizabeth Eshel, Najib Dally, Martin Ruthardt, Jamal Mahajna
Philadelphia chromosome-positive (Ph+) leukemia is characterized by reciprocal translocation between chromosomes 9 and 22. The resultant BCR/ABL fusion protein displays constitutive tyrosine kinase activity, leading to the induction of aberrant proliferation and neoplastic transformation. The bone marrow (BM) microenvironment is tumor-promoting, and contributes to disease recurrence in Ph+ leukemia. Activity in the BM microenvironment is mediated by several cellular compartments, extracellular matrix, various soluble factors including transforming growth factor beta 1 (TGF-β1), and the hypoxic conditions in the BM niche...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29181139/outcome-of-frontline-treatment-with-generic-imatinib-in-adult-patients-with-chronic-myeloid-leukemia-in-algerian-population-a-multicenter-study
#9
B Entasoltan, M A Bekadja, H Touhami, N Mehalhal, Z Zouaoui, N Mesli, M Talbi, A Bachiri, M Michallet
Introduction: In a developing country like Algeria, such expensive therapy is not available. Alternative approaches are needed to help these adult. In Algeria 'imatib' (CIPLA-India) was introduced in 2006; but no study has been published yet in the North Africa region regarding response and outcome of this copy in CML patients. The goal of this multicenter study is to characterize newly adult CML in the western region of Algeria and to assess the effectiveness and safety of imatib (IM, copy) as frontline therapy for patients with CML...
2017: Mediterranean Journal of Hematology and Infectious Diseases
https://www.readbyqxmd.com/read/29169426/-knockdown-of-alox5-gene-promotes-apoptosis-of-k562-adm-cells
#10
Yujie Luo, Min Xu, Wenwan Gao, Kun Tao
Objective To investigate the effect of short hairpin RNA (shRNA) knockdown of arachidonate 5-lipoxygenase (Alox5) gene on the apoptosis of resistant chronic myeloid leukemia K562/ADM cells. Methods Three pairs of shRNA fragment targeting human Alox5 gene were synthesized and inserted into pGenesil-1 interference vector. Enzyme digestion and sequencing were performed to identify the recombinant plasmid pGenesil-1-shRNA-Alox5. The plasmid was then transfected into K562/ADM cells. Real-time quantitative PCR and Western blotting were used to detect the Alox5 mRNA and protein levels to get the best interference group...
October 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/29165716/targeting-bcr-abl-independent-tki-resistance-in-chronic-myeloid-leukemia-by-mtor-and-autophagy-inhibition
#11
Rebecca Mitchell, Lisa E M Hopcroft, Pablo Baquero, Elaine K Allan, Kay Hewit, Daniel James, Graham Hamilton, Arunima Mukhopadhyay, Jim O'Prey, Alan Hair, Junia V Melo, Edmond Chan, Kevin M Ryan, Véronique Maguer-Satta, Brian J Druker, Richard E Clark, Subir Mitra, Pawel Herzyk, Franck E Nicolini, Paolo Salomoni, G Vignir Helgason
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment...
November 20, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29152650/semi%C3%A2-random-mutagenesis-profile-of-bcr%C3%A2-abl-during-imatinib-resistance-acquirement-in-k562-cells
#12
Yan Dong, Xiaotong Gao, Yingxin Zhao, Mengying Wei, Lingmin Xu, Guodong Yang, Li Liu
Although imatinib is effective in chronic myeloid leukemia treatment, imatinib resistance due to the T315I mutation and/or other mutations is a challenge to be overcome. However, how DNA mutation occurs, particularly the T315I mutation, remains unclear. In the current study, the mutagenesis of BCR‑ABL was analyzed via focusing on the process of drug resistance, rather than the final results. Clone sequencing of the BCR‑ABL gene and other control genes was applied in two imatinib‑resistant cell models...
October 19, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29152059/gzd824-suppresses-the-growth-of-human-b-cell-precursor-acute-lymphoblastic-leukemia-cells-by-inhibiting-the-src-kinase-and-pi3k-akt-pathways
#13
Wei Ye, Zhiwu Jiang, Xiaoyun Lu, Xiaomei Ren, Manman Deng, Shouheng Lin, Yiren Xiao, Simiao Lin, Suna Wang, Baiheng Li, Yi Zheng, Peilong Lai, Jianyu Weng, Donghai Wu, Yuguo Ma, Xudong Chen, Zhesheng Wen, Yaoyu Chen, Xiaoyan Feng, Yangqiu Li, Pentao Liu, Xin Du, Duanqing Pei, Yao Yao, Bing Xu, Ke Ding, Peng Li
Available therapeutic options for advanced B cell precursor acute lymphoblastic leukemia (pre-B ALL) are limited. Many lead to neutropenia, leaving patients at risk of life-threatening infections and result in bad outcomes. New treatment options are needed to improve overall survival. We previously showed that GZD824, a novel BCR-ABL tyrosine kinase inhibitor, has anti-tumor activity in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia cells and tumor models. Here, we show that GZD824 decreases cell viability, induces cell-cycle arrest, and causes apoptosis in pre-B ALL cells...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29151902/coexistence-of-p210bcr-abl-and-cbf%C3%AE-myh11-fusion-genes-in-myeloid-leukemia-a-report-of-4-cases
#14
Yuan-Yuan Wang, Wen-Jing Ding, Feng Jiang, Zi-Xing Chen, Jian-Nong Cen, Xiao-Fei Qi, Jian-Ying Liang, Dan-Dan Liu, Jin-Lan Pan, Su-Ning Chen
Numerous acquired molecular and cytogenetic abnormalities are strongly associated with hematological malignancies. The breakpoint cluster region-ABL proto-oncogene 1 (BCR-ABL) rearrangement leads to a p210 chimeric protein in typical chronic myeloid leukemia (CML), whereas 17-25% of patients with acute lymphocytic leukemia and 0.9-3% patients with de novo acute myeloid leukemia (AML) carry a p190BCR-ABL fusion protein. Cases of patients with AML/CML carrying two specific primary molecular changes, BCR-ABL and core binding factor-β-myosin heavy chain 11 (CBFβ-MYH11) fusion genes have been rarely reported...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29149649/chk1-inhibitors-overcome-imatinib-resistance-in-chronic-myeloid-leukemia-cells
#15
Hu Lei, Jin Jin, Meng Liu, Xiangyun Li, Hao Luo, Li Yang, Hanzhang Xu, Yingli Wu
Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem of chronic myelogenous leukemia (CML). Bcr-Abl protein depletion is considered as a way to overcome drug resistance to TKIs. In our study, Chk1 inhibitors, AZD7762 and MK-8776, had strong antitumor effects on CML cell line KBM5 and imatinib-resistant form KBM5T315I. Moreover, Chk1 inhibitors showed a strong cytotoxic effect on leukemia cells from primary CML and imatinib-resistance CML patients, but low cytotoxic effect on normal human mononuclear cells...
November 11, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29138846/itr%C3%A2-284-modulates-cell-differentiation-in-human-chronic-myelogenous-leukemia-k562-cells
#16
Jai-Sing Yang, Chao-Ying Lee, Hsin-Chung Cho, Chi-Cheng Lu, Sheng-Chu Kuo, Yen-Fang Wen, Fuu-Jen Tsai, Miau-Rong Lee, Shih-Chang Tsai
ITR‑284 is a carboxamide analog that can inhibit proliferation in human promyelocytic leukemia HL-60 cells. To understand the effects and molecular mechanisms of ITR‑284 in human erythromyeloblastoid leukemia, we treated K562 cells with different concentrations of ITR‑284 (0, 2, 4, 6, 8 and 10 nM) and all-trans retinoic acid (ATRA) (0, 0.1, 0.5, 1, 5 and 10 µM) for 24 h. The IC50 of ITR‑284 was ~10 nM in K562 cells treated for 24 h as determined by MTT assay. May-Grünwald-Giemsa staining and nitro blue tetrazolium (NBT) assays were used to determine cell morphology changes and differentiation after ITR‑284 and ATRA treatment...
November 9, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29138221/immature-cml-cells-implement-a-bmp-autocrine-loop-to-escape-tki-treatment
#17
Elodie Grockowiak, Bastien Laperrousaz, Sandrine Jeanpierre, Thibault Voeltzel, Boris Guyot, Stéphanie Gobert, Franck E Nicolini, Véronique Maguer-Satta
The BCR-ABL specific Tyrosine Kinase Inhibitors (TKI) changed the outcome of Chronic Myeloid Leukemia (CML), turning a life-threatening disease into a chronic illness. However, TKI are not yet curative, since most patients retain leukemic stem cells (LSC) and their progenitors in bone marrow and relapse following treatment cessation. At diagnosis, deregulations of the Bone Morphogenetic Proteins (BMP) pathway are involved in LSC and progenitors expansion. Here, we report that BMP pathway alterations persist in TKI-resistant patients...
November 14, 2017: Blood
https://www.readbyqxmd.com/read/29127384/targeting-c-kit-cd117-by-dasatinib-and-radotinib-promotes-acute-myeloid-leukemia-cell-death
#18
Sook-Kyoung Heo, Eui-Kyu Noh, Jeong Yi Kim, Yoo Kyung Jeong, Jae-Cheol Jo, Yunsuk Choi, SuJin Koh, Jin Ho Baek, Young Joo Min, Hawk Kim
Dasatinib and radotinib are oral BCR-ABL tyrosine kinase inhibitors that were developed as drugs for the treatment of chronic myeloid leukemia. We report here that the c-KIT (CD117) targeting with dasatinib and radotinib promotes acute myeloid leukemia (AML) cell death, and c-KIT endocytosis is essential for triggering c-KIT-positive AML cell death by dasatinib and radotinib during the early stages. In addition, dasatinib and radotinib reduce heat shock protein 90β (HSP90β) expression and release Apaf-1 in c-KIT-positive AML cells...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29121435/altered-intracellular-signaling-by-imatinib-increases-the-anti-cancer-effects-of-tyrosine-kinase-inhibitors-in-cml-cells
#19
Takuya Hirao, Masashi Yamaguchi, Megumi Kikuya, Hiroji Chibana, Kousei Ito, Shigeki Aoki
Tyrosine kinase inhibitors (TKIs), including imatinib (IM), improve the outcome of chronic myelogenous leukemia (CML) therapy. However, TKI treatment is long-term and can induce resistance to TKIs, which often leads to a poor clinical outcome in CML patients. Here, we examined the effect of continuous IM exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome-positive CML cell line, and its subsequent sensitivity to anti-cancer agents. Contrary to our expectations, we found that continuous IM exposure increased sensitivity to TKIs...
November 9, 2017: Cancer Science
https://www.readbyqxmd.com/read/29113191/how-to-detect-the-rare-bcr-abl-e14a3-transcript-a-case-report-and-literature-review
#20
Lin-Hui Hu, Lian-Fang Pu, Dong-Dong Yang, Cui Zhang, Hui-Ping Wang, Yang-Yang Ding, Man-Man Li, Zhi-Min Zhai, Shudao Xiong
The Philadelphia (Ph; BCR-ABL) chromosome originates from a translocation event between chromosomes 9 and 22, and results in the BCR-ABL fusion gene. In chronic myelogenous leukemia (CML), the BCR-ABL gene is mainly coded for by a major breakpoint cluster region (M-bcr, e13a2 and e14a2). However, in some patients, BCR-ABL genes are encoded by a minor (m)-bcr, e1a2, and a micro (µ)-bcr region, e19a2. These transcripts revealed a different clinical course. The present study described a CML patient whose cytogenetics and FISH analyses of bone marrow revealed a karyotype of 46, XY t(9,22) (q34;q11), while the commercial kits of quantitative PCR (qPCR) failed to detect the BCR-ABL fusion gene...
November 2017: Oncology Letters
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