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https://www.readbyqxmd.com/read/28431398/decreased-calpain-activity-in-chronic-myeloid-leukemia-impairs-apoptosis-by-increasing-survivin-in-myeloid-progenitors-and-xiap1-in-differentiating-granulocytes
#1
Weiqi Huang, Ling Bei, Elizabeth E Hjort, Elizabeth A Eklund
Chronic Myeloid Leukemia (CML) is characterized by translocations between chromosomes 9 and 22, resulting in expression of Bcr-abl oncogenes. Although the clinical course of CML was revolutionized by development of Bcr-abl-directed tyrosine kinase inhibitors (TKIs), CML is not cured by these agents. Specifically, the majority of subjects relapsed in clinical trials attempting TKI discontinuation, suggesting persistence of leukemia stem cells (LSCs) even in molecular remission. Identifying mechanisms of CML-LSC persistence may suggest rationale therapeutic targets to augment TKI efficacy and lead to cure...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28428616/cancer-belt-and-braces-for-bcr-abl
#2
Megan Cully
No abstract text is available yet for this article.
April 21, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28423730/the-sclttaxbcr-abl-transgenic-mouse-model-closely-reflects-the-differential-effects-of-dasatinib-on-normal-and-malignant-hematopoiesis-in-chronic-phase-cml-patients
#3
Claudia Schubert, Nicolas Chatain, Till Braunschweig, Mirle Schemionek, Kristina Feldberg, Melanie Hoffmann, Olli Dufva, Satu Mustjoki, Tim H Brümmendorf, Steffen Koschmieder
The second generation tyrosine kinase inhibitor (TKI) dasatinib is a clinically approved drug for chronic myeloid leukemia (CML) as well as Ph+ acute lymphoblastic leukemia. In addition to its antileukemic effects, dasatinib was shown to impact on normal hematopoiesis and cells of the immune system.Due to the fact that the murine in vivo studies so far have not been performed in a chronic-phase CML model under steady-state conditions, our aim was to study the hematopoietic effects of dasatinib (20 mg/kg p.o...
March 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28409295/metal-chelator-tpen-selectively-induces-apoptosis-in-k562-cells-through-reactive-oxygen-species-signaling-mechanism-implications-for-chronic-myeloid-leukemia
#4
Luisa Rojas-Valencia, Carlos Velez-Pardo, Marlene Jimenez-Del-Rio
Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the constitutive expression of BCR-ABL tyrosine kinase. Although successful implementation of tyrosine kinase inhibitors for the treatment of CML remain a traditional choice for molecularly targeted therapy, some patients present primary or secondary resistance to such therapy. Therefore, alternative therapeutic strategies are required to treat resistant CML cells. Accordingly, new anti-proliferative and/or pro-apoptotic compounds would be needed for clinical treatment...
April 13, 2017: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/28406068/clinical-and-hematological-relevance-of-jak2-v617f-and-calr-mutations-in-bcr-abl-negative-et-patients
#5
N Limsuwanachot, B Rerkamnuaychoke, S Chuncharunee, T Pauwilai, R Singdong, P Rujirachaivej, T Chareonsirisuthigul, T Siriboonpiputtana
BACKGROUND: Classical BCR-ABL1-negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis frequently harbor JAK2, MPL, and CALR somatic mutations. METHODS: AS-PCR for JAK2 V617F, pyrosequencing for MPL W515L/K, and PCR-fragment analysis for CALR exon 9 mutations were established to analyze genomic DNA isolated from peripheral blood samples of 58 newly diagnosed ET patients in Thailand. RESULTS: JAK2 V617F was detected in 41 patients (71%) and CALR exon 9 mutation was positive in eight patients (14%), whereas no mutation of MPL W515L/K was observed in this study...
April 13, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28404889/cryptic-bcr-abl-fusion-gene-as-variant-rearrangement-in-chronic-myeloid-leukemia-molecular-cytogenetic-characterization-and-influence-on-tkis-therapy
#6
Simona Luatti, Carmen Baldazzi, Giulia Marzocchi, Gaia Ameli, Maria Teresa Bochicchio, Simona Soverini, Fausto Castagnetti, Mario Tiribelli, Gabriele Gugliotta, Giovanni Martinelli, Michele Baccarani, Michele Cavo, Gianantonio Rosti, Nicoletta Testoni
At diagnosis, about 5% of Chronic Myeloid Leukemia (CML) patients lacks Philadelphia chromosome (Ph), despite the presence of the BCR/ABL rearrangement. Two mechanisms have been proposed about the occurrence of this rearrangement: the first one is a cryptic insertion between chromosomes 9 and 22; the second one involves two sequential translocations: a classic t(9;22) followed by a reverse translocation, which reconstitutes the normal morphology of the partner chromosomes. Out of 398 newly diagnosed CML patients, we selected 12 Ph-negative cases...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28403779/design-synthesis-and-biological-evaluation-of-betulinic-acid-derivatives-as-new-antitumor-agents-for-leukemia
#7
Fernanda Waechter, Gloria Santos Silva, Julia Willig, Cristiane Bernardes de Oliveira, Bruna Domingues Vieira, Daniela Barreto Trivella, Aline Rigon Zimmer, Andréia Buffon, Diogo André Pilger, Simone Gnoatto
Chronic myeloid leukemia (CML) is currently treated with imatinib, a Bcr-Abl inhibitor. However, resistance to this drug usually develops over time. Triptolide, a diterpenoid triepoxide, has been shown active against CML cells resistant to imatinib, acting mainly on the level of Bcr-Abl transcription inhibition. Here, we used the triterpene betulinic acid, a known proteasome inhibitor with potential antileukemic activity, as a scaffold for the generation of analogues with predicted triptolide biological activity...
April 12, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28396095/elderly-patients-with-chronic-myeloid-leukemia-benefit-from-a-dasatinib-dose-as-low-as-20-mg
#8
Hidekazu Itamura, Yasushi Kubota, Takero Shindo, Toshihiko Ando, Kensuke Kojima, Shinya Kimura
BACKGROUND: The clinical outcomes of patients with chronic myeloid leukemia (CML) treated with BCR-ABL tyrosine kinase inhibitors has improved markedly; however, the occurrence of adverse events (AEs) means that elderly patients often cannot be administered the standard dose. Nevertheless, some patients treated with low doses of tyrosine kinase inhibitor have achieved good molecular responses. PATIENTS AND METHODS: We retrospectively analyzed the efficacy and safety of low-dose dasatinib treatment of elderly CML patients...
March 18, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28390196/pi3k-isoform-inhibition-associated-with-anti-bcr-abl-drugs-shows-in-vitro-increased-anti-leukemic-activity-in-philadelphia-chromosome-positive-b-acute-lymphoblastic-leukemia-cell-lines
#9
Simona Ultimo, Carolina Simioni, Alberto M Martelli, Giorgio Zauli, Camilla Evangelisti, Claudio Celeghini, James A McCubrey, Giorgia Marisi, Paola Ulivi, Silvano Capitani, Luca M Neri
B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28387439/oncophosphosignaling-favors-a-glycolytic-phenotype-in-human-drug-resistant-leukemia
#10
Alessandra V S Faria, Thaís F Tornatore, Renato Milani, Karla C S Queiroz, Igor H Sampaio, Emanuella M B Fonseca, Karin J P Rocha-Brito, Tamira Oliveira Santos, Leonardo R Silveira, Maikel P Peppelenbosch, Carmen Veríssima Ferreira-Halder
In chemoresistant leukemia cells (Lucena-1), the low molecular weight protein tyrosine phosphatase (LMWPTP) is about 20-fold more active than in their susceptible counterpart (K562). We found this phosphatase ensures the activated statuses of Src and Bcr-Abl. Since phosphorylation and dephosphorylation of proteins represent a key post-translational regulation of several enzymes, we also explored the kinome. We hereby show that LMWPTP superactivation, together with kinome reprogramming, cooperate towards glucose addiction...
April 7, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28384883/dasatinib-induced-cardiac-tamponade-a-rare-association
#11
Sushant Wattal, Mugula Sudhakar Rao, Gs Naveen Chandra, U K Abdul Razak, K Ranjan Shetty
Drug induced cardiac tamponade is rare. Therapy for imatinib resistant Chronic Myeloid Leukaemia (CML) is an emerging challenge in clinical haematology. For such cases treatment with second line tyrosine kinase inhibitors like dasatinib has resulted in improved outcomes. Dasatinib is a second line BCR-ABL tyrosine kinase inhibitor used in the treatment of Imatinib resistant or Imatinib intolerant CML. Dasatinib has been reported to cause severe pericardial effusions in 1% of all patients in clinical studies...
February 2017: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28377326/treatment-and-molecular-monitoring-update-in-chronic-myeloid-leukemia-management
#12
Nathalie Sorel, Émilie Cayssials, Françoise Brizard, Jean-Claude Chomel
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from the t(9;22)(q34;q11) translocation. It is characterized by the presence of the BCR-ABL1 fusion gene encoding the BCR-ABL oncoprotein characterized by a deregulated tyrosine kinase activity. Targeted therapies using tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib, bosutinib, or ponatinib have profoundly changed the natural history of the disease with a major impact on survival. Indeed, most patients diagnosed today can enjoy a near normal life expectancy...
April 1, 2017: Annales de Biologie Clinique
https://www.readbyqxmd.com/read/28372728/determination-of-cdna-encoding-bcr-abl-fusion-gene-in-patients-with-chronic-myelogenous-leukemia-using-a-novel-fret-based-quantum-dots-dna-nanosensor
#13
Mojtaba Shamsipur, Vahid Nasirian, Ali Barati, Kamran Mansouri, Asad Vaisi-Raygani, Soheila Kashanian
In the present study, we developed a sensitive method based on fluorescence resonance energy transfer (FRET) for the determination of the BCR/ABL fusion gene, which is used as a biomarker to confirm the clinical diagnosis of both chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). For this purpose, CdTe quantum dots (QDs) were conjugated to amino-modified 18-mer oligonucleotide ((N)DNA) to form the QDs-(N)DNA nanosensor. In the presence of methylene blue (MB) as an intercalator, the hybridization of QDs-(N)DNA with the target BCR/ABL fusion gene (complementary DNA), brings the MB (acceptor) at close proximity of the QDs (donor), leading to FRET upon photoexcitation of the QDs...
May 8, 2017: Analytica Chimica Acta
https://www.readbyqxmd.com/read/28370510/socio-economic-burden-of-participation-in-clinical-trials-in-patients-with-myeloproliferative-neoplasms
#14
Swati Goel, Chiara Paoli, Alessandra Iurlo, Arturo Pereira, Fabio Efficace, Tiziano Barbui, Ayalew Tefferi, Alessandro M Vannucchi, Francisco Cervantes
OBJECTIVE: To determine the financial and psycho-social impact of participation in clinical trials of patients with BCR/ABL-negative myeloproliferative neoplasms (MPN). METHODS: An international, observational cross section study was performed in 143 consecutive MPN patients (51% myelofibrosis, 36% polycythemia vera, 13% essential thrombocythemia), 68% from Italy, 17% from USA, and 15% from Spain. RESULTS: Thirty-five percent of patients reported having spent more money during the trial than in previous treatments and 21% having missed more workdays...
March 31, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28366933/a-novel-ahi-1-bcr-abl-dnm2-complex-regulates-leukemic-properties-of-primitive-cml-cells-through-enhanced-cellular-endocytosis-and-ros-mediated-autophagy
#15
X Liu, K Rothe, R Yen, C Fruhstorfer, T Maetzig, M Chen, D L Forrest, K Humphries, X Jiang
Tyrosine kinase inhibitor (TKI) therapies induce clinical remission with remarkable effects on chronic myeloid leukemia (CML). However, very few TKIs completely eradicate the leukemic clone and persistence of leukemic stem cells (LSCs) remains challenging, warranting new, distinct targets for improved treatments. We demonstrated that the scaffold protein AHI-1 is highly deregulated in LSCs and interacts with multiple proteins, including Dynamin-2 (DNM2), to mediate TKI-resistance of LSCs. We have now demonstrated that the SH3 domain of AHI-1 and the proline rich domain of DNM2 are mainly responsible for this interaction...
April 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28365527/imatinib-discontinuation-in-chronic-myeloid-leukaemia-patients-with-undetectable-bcr-abl-transcript-level-a%C3%A2-systematic-review-and-a-meta-analysis
#16
REVIEW
Leonardo Campiotti, Matteo Basilio Suter, Luigina Guasti, Rocco Piazza, Carlo Gambacorti-Passerini, Anna Maria Grandi, Alessandro Squizzato
PURPOSE: Tyrosine kinase inhibitors (TKIs) are the cornerstones of treatment for patients with chronic myeloid leukaemia (CML). In recent years, several studies were conducted to evaluate the safety of TKIs discontinuation. We performed a systematic review of the literature to determine the incidence of CML relapse, to identify possible factors relapse rates and to evaluate the long-term safety in CML patients with stable undetectable BCR-ABL transcript level who discontinued TKIs. DESIGN: Studies evaluating TKIs discontinuation in CML patients with undetectable BCR-ABL transcript level were identified by electronic search of MEDLINE and EMBASE database until May 2015...
March 30, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28355131/silencing-of-bcr-abl-chimeric-gene-in-human-chronic-myelogenous-leukemia-cell-line-k562-by-sirna-nuclear-export-signal-peptide-conjugates
#17
Yasuhiro Shinkai, Shinichi Kashihara, Go Minematsu, Hirofumi Fujii, Madoka Naemura, Yojiro Kotake, Yasutaka Morita, Koichiro Ohnuki, Alesya A Fokina, Dmitry A Stetsenko, Vyacheslav V Filichev, Masayuki Fujii
Herein we described the synthesis of siRNA-NES (nuclear export signal) peptide conjugates by solid phase fragment coupling and the application of them to silencing of bcr/abl chimeric gene in human chronic myelogenous leukemia cell line K562. Two types of siRNA-NES conjugates were prepared, and both sense strands at 5' ends were covalently linked to a NES peptide derived from TFIIIA and HIV-1 REV, respectively. Significant enhancement of silencing efficiency was observed for both of them. siRNA-TFIIIA NES conjugate suppressed the expression of BCR/ABL gene to 8...
March 29, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28349229/mpt0b002-a-novel-microtubule-inhibitor-downregulates-t315i-mutant-bcr-abl-and-induces-apoptosis-of-imatinib-resistant-chronic-myeloid-leukemia-cells
#18
Yi-Yen Yeh, Jing-Ping Liou, Yueh-Lun Lee, John Yi-Chung Lin, Huei-Mei Huang
Chronic myeloid leukemia (CML) is a hematopoietic malignancy caused by the constitutive activation of Bcr-Abl tyrosine kinase. The Bcr-Abl inhibitor imatinib and other second-generation tyrosine kinase inhibitors such as dasatinib and nilotinib have remarkable efficacy in CML treatment. However, gene mutation-mediated drug resistance remains a critical problem. Among point mutations, the Bcr-Abl T315I mutation confers resistance to these Bcr-Abl inhibitors. Previously, we have synthesized the compound (1-methyl-1H-indol-5-yl)-(3,4,5-trimethoxy-phenyl)-methanone (MPT0B002) as a novel microtubule inhibitor...
March 27, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28345463/computational-and-mechanistic-studies-on-the-effect-of-galactoxyloglucan-imatinib-nanoconjugate-in-imatinib-resistant-k562-cells
#19
Alphy Rose James, B S Unnikrishnan, R Priya, Manu M Joseph, T K Manojkumar, K Raveendran Pillai, R Shiji, G U Preethi, P Kusumakumary, T T Sreelekha
Imatinib mesylate, a BCR/ABL fusion protein inhibitor, is the first-line treatment against chronic myelogenous leukemia. In spite of its advantageous viewpoints, imatinib still has genuine impediments like undesirable side effects and tumor resistance during chemotherapy. Nanoparticles with sustainable release profile will help in targeted delivery of anticancer drugs while minimizing deleterious side effects and drug resistance. The use of biopolymers like galactoxyloglucan (PST001) for the fabrication of imatinib mesylate nanoparticles could impart its use in overcoming multidrug resistance in chronic myelogenous leukemia patients with minimal side effects...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28340692/calr-gene-mutational-profile-in-myeloproliferative-neoplasms-with-non-mutated-jak2-in-moroccan-patients-a-case-series-and-germline-in-frame-deletion
#20
W Smaili, Y Doubaj, F Z Laarabi, J Lyahyai, M Kerbout, M Mikdame, A Sefiani
BACKGROUND: The discovery of somatic mutations within the gene encoding calreticulin (CALR) in 2013 represented a major milestone in the molecular diagnosis of BCR-ABL negative myeloproliferative neoplasms (MPN). In fact, exome sequencing revealed that most patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF) lacking JAK2 or MPL mutations, harbor somatic insertion and/or deletion in exon 9 of CALR gene. In this study, we identified the first CALR gene mutational landscape in Moroccan patients with MPN nonmutated for the JAK2 gene...
January 2017: Current Research in Translational Medicine
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