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Leukemia chemoresistance

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https://www.readbyqxmd.com/read/29669823/recurrent-patterns-of-protein-expression-signatures-in-pediatric-acute-lymphoblastic-leukemia-recognition-and-therapeutic-guidance
#1
Fieke W Hoff, Chenyue W Hu, Yihua Qiu, Andrew Ligeralde, Suk-Young Yoo, Eveline Sjm De Bont, Amina A Qutub, Terzah M Horton, Steven M Kornblau
Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, and the second leading cause of pediatric cancer death in developed countries. While the cure rate for newly-diagnosed ALL is excellent, the genetic heterogeneity and chemoresistance of leukemia cells at relapse makes individualized curative treatment plans difficult. We hypothesize that genetic events would coalesce into a finite number of protein signatures that could guide the design of individualized therapy. Custom Reverse Phase Protein Arrays were produced from pediatric ALL (n=73) and normal CD34+ (n=10) samples with 194 validated antibodies...
April 18, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29663500/knockdown-of-lncrna-uca1-suppresses-chemoresistance-of-pediatric-aml-by-inhibiting-glycolysis-through-the-microrna-125a-hexokinase-2-pathway
#2
Yuan Zhang, Yufeng Liu, Xueju Xu
Dysregulation of lncRNAs is implicated in chemoresistance in varieties of tumor including acute myeloid leukemia (AML). LncRNA urothelial carcinoma-associated 1 (UCA1) was reported to play an oncogenic role in AML. However, whether UCA1 was involved in chemoresistance in pediatric AML remains unclear. UCA1 expression in AML patients after adriamycin (ADR)-based chemotherapy and ADR-resistant AML cells was examined by qRT-PCR. The effects of UCA1 on the cytotoxicity of ADR and glycolysis were evaluated by MTT assay and measuring the glucose consumption and lactate production in HL60 and HL60/ADR cells, repectively...
April 16, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29616858/role-of-yin-yang-1-yy1-in-the-transcription-regulation-of-the-multi-drug-resistance-mdr1-gene
#3
Gabriela Antonio-Andrés, Jesus Rangel-Santiago, Belen Tirado-Rodríguez, Gustavo U Martinez-Ruiz, Miguel Klunder-Klunder, Mario I Vega, Briceida Lopez-Martinez, Elva Jiménez-Hernández, Jose Torres Nava, Aurora Medina-Sanson, Sara Huerta-Yepez
Resistance to chemotherapy hinders the successful treatment of acute lymphoblastic leukemia (ALL). The multi-drug resistance-1 (MDR1/ABCB1) gene encodes P-glycoprotein (P-gp), which plays an important role in chemoresistance; however, its transcriptional regulation remains unclear. We investigated the role of YY1 in the regulation of MDR1 and its relation to ALL outcomes. Analysis of the MDR1 promoter revealed four putative YY1-binding sites, which we analyzed using a reporter system and ChIP analysis. YY1 silencing resulted in the inhibition of MDR1 expression and function...
April 4, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29580029/osteopontin-b-and-c-splice-isoforms-in-leukemias-and-solid-tumors-angiogenesis-alongside-chemoresistance
#4
REVIEW
Akram Mirzaei, Saeed Mohammadi, Seyed H Ghaffari, Marjan Yaghmaie, Mohammad Vaezi, Kamran Alimoghaddam, Ardeshir Ghavamzadeh
Osteopontin (OPN) is a glycoprotein involved in regulation of various influences on tumor progression, such as cellular proliferation, apoptosis, angiogenesis, and metastasis. Vascular endothelial growth factor (VEGF) is a secreted molecule supporting angiogenesis in various cancers through activation of the PI3K/AKT/ERK1/2 pathway. OPN and VEGF have a number of isoforms with various activities. In spite of the well-defined association between OPN and VEGF isoform expression and cure rate for solid tumors, there is a scarcity of information as to any association in leukemia...
March 27, 2018: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/29576448/dual-inhibition-of-pi3k-mtor-signaling-in-chemoresistant-aml-primary-cells
#5
Jessika Bertacchini, Chiara Frasson, Francesca Chiarini, Daniele D'Avella, Benedetta Accordi, Laura Anselmi, Patrizia Barozzi, Fabio Foghieri, Mario Luppi, Alberto M Martelli, Giuseppe Basso, Saki Najmaldin, Abbas Khosravi, Fakher Rahim, Sandra Marmiroli
A main cause of treatment failure for AML patients is resistance to chemotherapy. Survival of AML cells may depend on mechanisms that elude conventional drugs action and/or on the presence of leukemia initiating cells at diagnosis, and their persistence after therapy. MDR1 gene is an ATP-dependent drug efflux pump known to be a risk factor for the emergence of resistance, when combined to unstable cytogenetic profile of AML patients. In the present study, we analyzed the sensitivity to conventional chemotherapeutic drugs of 26 samples of primary blasts collected from AML patients at diagnosis...
March 19, 2018: Advances in Biological Regulation
https://www.readbyqxmd.com/read/29552172/effects-of-nvp-bez235-a-dual-phosphatidylinositol-3-kinase-mammalian-target-of-rapamycin-inhibitor-on-htlv-1-infected-t-cell-lines
#6
Chie Ishikawa, Masachika Senba, Naoki Mori
Adult T-cell leukemia (ATL) is an aggressive type of malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). In ATL, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is constitutively active, promoting cell proliferation, survival and chemoresistance. Thus, the PI3K signaling pathway is an attractive therapeutic target for ATL. In the present study, the effects of RAD001 (an mTOR inhibitor), NVP-BKM120 (a pan-PI3K inhibitor) and NVP-BEZ235 (a novel dual PI3K/mTOR inhibitor) on cultured HTLV-1-infected T-cell lines were compared...
April 2018: Oncology Letters
https://www.readbyqxmd.com/read/29535428/relapsed-acute-lymphoblastic-leukemia-specific-mutations-in-nt5c2-cluster-into-hotspots-driving-intersubunit-stimulation
#7
Aleš Hnízda, Milan Fábry, Takaya Moriyama, Petr Pachl, Michael Kugler, Vítězslav Brinsa, David B Ascher, William L Carroll, Petr Novák, Markéta Žaliová, Jan Trka, Pavlína Řezáčová, Jun J Yang, Václav Veverka
Activating mutations in NT5C2, a gene encoding cytosolic purine 5'-nucleotidase (cN-II), confer chemoresistance in relapsed acute lymphoblastic leukemia. Here we show that all mutants became independent of allosteric effects of ATP and thus constitutively active. Structural mapping of mutations described in patients demonstrates that 90% of leukemia-specific allelles directly affect two regulatory hotspots within the cN-II molecule-the helix A region: residues 355-365, and the intersubunit interface: helix B (232-242) and flexible interhelical loop L (400-418)...
February 25, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29519869/dexamethasone-in-hyperleukocytic-acute-myeloid-leukemia
#8
Sarah Bertoli, Muriel Picard, Emilie Bérard, Emmanuel Griessinger, Clément Larrue, Pierre-Luc Mouchel, François Vergez, Suzanne Tavitian, Edwige Yon, Jean Ruiz, Eric Delabesse, Isabelle Luquet, Laetitia Karine Linares, Estelle Saland, Martin Carroll, Gwenn Danet-Desnoyers, Audrey Sarry, Françoise Huguet, Jean-Emmanuel Sarry, Christian Récher
Patients with acute myeloid leukemia and a high white blood cell count are at increased risk for early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50x109 white blood cells. In silico studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone...
March 8, 2018: Haematologica
https://www.readbyqxmd.com/read/29515335/differential-mrna-expression-of-the-main-apoptotic-proteins-in-normal-and-malignant-cells-and-its-relation-to-in-vitro-resistance
#9
Andrea Vazanova, Jana Jurecekova, Tomas Balharek, Juraj Marcinek, Jan Stasko, Anton Dzian, Lukas Plank, Pavol Zubor, Peter Racay, Jozef Hatok
Background: Apoptosis plays an important role in the development and homeostasis of multicellular organisms and its deregulation may result in many serious diseases, including cancer. Now it is clear that some oncogenic mutations disrupt apoptosis, leading to tumour initiation, progression or metastasis. Here, expression of apoptotic genes in context of drug resistance was investigated. Methods: We examined total of 102 samples from leukemic patients (n = 60) and patients with solid tumours (n = 42)...
2018: Cancer Cell International
https://www.readbyqxmd.com/read/29514855/the-novel-c-terminal-truncated-90-kda-isoform-of-topoisomerase-ii%C3%AE-top2%C3%AE-90-is-a-determinant-of-etoposide-resistance-in-k562-leukemia-cells-via-heterodimerization-with-the-top2%C3%AE-170-isoform
#10
Ragu Kanagasabai, Soumendrakrishna Karmahapatra, Corey A Kientz, Yang Yu, Victor A Hernandez, Evan E Kania, Terry S Elton, Jack C Yalowich
DNA topoisomerase IIα (170 kDa, TOP2α/170) is essential in proliferating cells by resolving DNA topological entanglements during chromosome condensation, replication, and segregation. We previously characterized a C-terminally truncated isoform (TOP2α/90), detectable in human leukemia K562 cells but more abundantly expressed in a clonal subline, K/VP.5, with acquired resistance to the anticancer agent etoposide. TOP2α/90 (786 aa) is the translation product of a TOP2α mRNA which retains a processed intron 19...
March 7, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29496539/sabutoclax-pan-active-bcl-2-protein-family-antagonist-overcomes-drug-resistance-and-eliminates-cancer-stem-cells-in-breast-cancer
#11
Yunhui Hu, Ernesto Yagüe, Jing Zhao, Luyao Wang, Jingchao Bai, Qianxi Yang, Teng Pan, Hui Zhao, Jingjing Liu, Jin Zhang
Misregulation of BCL-2 family of proteins renders a survival signal to withstand cytotoxic anticancer drugs and is often found in drug resistant cells. The drug resistance phenotype is also associated with an enhancement of cancer stem cell-like (CSC) characteristics. Thus, inhibition of anti-apoptotic BCL-2 family proteins has been proposed as a possible antineoplastic strategy, and BCL-2 inhibitors are currently being clinically trailed in patients with leukemia, lymphoma or non-small cell lung cancer. However, the effects of BCL-2 inhibitors on drug resistant breast cancer have not yet been elucidated...
February 26, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29449434/msh6-haploinsufficiency-at-relapse-contributes-to-the-development-of-thiopurine-resistance-in-pediatric-b-lymphoblastic-leukemia
#12
Nikki A Evensen, P Pallavi Madhusoodhan, Julia Meyer, Jason Saliba, Ashfiyah Chowdhury, David J Araten, Jacob Nersting, Teena Bhatla, Tiffaney L Vincent, David Teachey, Stephen P Hunger, Jun Yang, Kjeld Schmiegelow, William L Carroll
Survival of children with relapsed acute lymphoblastic leukemia is poor and understanding mechanisms underlying resistance is essential in developing new therapy. Relapse-specific heterozygous deletions in MSH6, a crucial part of DNA Mismatch Repair, are frequently detected. Our aim was to determine whether MSH6 deletion results in a hypermutator phenotype associated with generation of secondary mutations involved in drug resistance or leads to a failure to initiate apoptosis directly in response to chemotherapeutic agents...
February 15, 2018: Haematologica
https://www.readbyqxmd.com/read/29445159/microfluidic-cell-sorting-by-stiffness-to-examine-heterogenic-responses-of-cancer-cells-to-chemotherapy
#13
Muhymin Islam, Roman Mezencev, Brynn McFarland, Hannah Brink, Betsy Campbell, Bushra Tasadduq, Edmund K Waller, Wilbur Lam, Alexander Alexeev, Todd Sulchek
Cancers consist of a heterogeneous populations of cells that may respond differently to treatment through drug-resistant sub-populations. The scarcity of these resistant sub-populations makes it challenging to understand how to counter their resistance. We report a label-free microfluidic approach to separate cancer cells treated with chemotherapy into sub-populations enriched in chemoresistant and chemosensitive cells based on the differences in cellular stiffness. The sorting approach enabled analysis of the molecular distinctions between resistant and sensitive cells...
February 14, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29435192/microrna-expression-and-activity-in-t-cell-acute-lymphoblastic-leukemia
#14
REVIEW
Fang Ye
T-cell acute lymphoblastic leukemia (T-ALL) is a lymphoid malignancy caused by the oncogenic transformation of immature T-cell progenitors. Many biologically relevant genetic and epigenetic alterations have been identified as driving factors for this transformation. Recently, microRNAs (miRNAs) have been shown to influence various leukemias, including T-ALL. Aberrant expression of miRNAs can function as either oncogenes or tumor suppressors in T-ALL through the regulation of cell migration, invasion, proliferation, apoptosis, and chemoresistance...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29431698/mef2c-phosphorylation-is-required-for-chemotherapy-resistance-in-acute-myeloid-leukemia
#15
Fiona C Brown, Eric Still, Richard P Koche, Christina Y Yim, Sumiko Takao, Paolo Cifani, Casie Reed, Shehana Gunasekera, Scott B Ficarro, Peter Romanienko, Willie Mark, Craig McCarthy, Elisa de Stanchina, Mithat Gonen, Venkatraman Seshan, Patrick Bhola, Conor O'Donnell, Barbara Spitzer, Crystal Stutzke, Vincent-Philippe Lavallée, Josée Hébert, Andrei V Krivstov, Ari Melnick, Elisabeth M Paietta, Martin S Tallman, Anthony Letai, Guy Sauvageau, Gayle Pouliot, Ross Levine, Jarrod A Marto, Scott A Armstrong, Alex Kentsis
In acute myeloid leukemia, chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2c S222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance, and induced by MARK kinases in cells...
February 5, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29427526/nup98-bptf-gene-fusion-identified-in-primary-refractory-acute-megakaryoblastic-leukemia-of-infancy
#16
Mathieu Roussy, Mélanie Bilodeau, Loubna Jouan, Pauline Tibout, Louise Laramée, Emmanuelle Lemyre, Sophie Cardin, Camille Sauvageau, Françoise Couture, Aurélien Choblet, Natalie Patey, Patrick Gendron, Michel Duval, Pierre Teira, Josée Hébert, Brian T Wilhelm, John K Choi, Tanja A Gruber, Henrique Bittencourt, Sonia Cellot
The advent of large scale genomic sequencing technologies significantly improved the molecular classification of acute megakaryoblastic leukaemia (AMKL). AMKL represents a subset (∼10%) of high fatality pediatric acute myeloid leukemia (AML). Recurrent and mutually exclusive chimeric gene fusions associated with pediatric AMKL are found in 60-70% of cases and include RBM15-MKL1, CBFA2T3-GLIS2, NUP98-KDM5A and MLL rearrangements. In addition, another 4% of AMKL harbor NUP98 rearrangements (NUP98r), with yet undetermined fusion partners...
February 10, 2018: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/29399180/characteristics-of-doxorubicin-selected-multidrug-resistant-human-leukemia-hl-60-cells-with-tolerance-to-arsenic-trioxide-and-contribution-of-leukemia-stem-cells
#17
Jing Chen, Hulai Wei, Jie Cheng, Bei Xie, Bei Wang, Juan Yi, Baoying Tian, Zhuan Liu, Feifei Wang, Zhewen Zhang
The present study selected and characterized a multidrug-resistant HL-60 human acute promyelocytic leukemia cell line, HL-60/RS, by exposure to stepwise incremental doses of doxorubicin. The drug-resistant HL-60/RS cells exhibited 85.68-fold resistance to doxorubicin and were cross-resistant to other chemotherapeutics, including cisplatin, daunorubicin, cytarabine, vincristine and etoposide. The cells over-expressed the transporters P-glycoprotein, multidrug-resistance-related protein 1 and breast-cancer-resistance protein, encoded by the adenosine triphosphate-binding cassette (ABC)B1, ABCC1 and ABCG2 genes, respectively...
January 2018: Oncology Letters
https://www.readbyqxmd.com/read/29382485/proteomic-changes-in-a-childhood-acute-lymphoblastic-leukemia-cell-line-during-the-adaptation-to-vincristine
#18
Ana Laura Guzmán-Ortiz, Gerardo Aparicio-Ozores, Ricardo Valle-Rios, Oscar Medina-Contreras, Genaro Patiño-López, Héctor Quezada
INTRODUCTION: Relapse occurs in approximately 20% of Mexican patients with childhood acute lymphoblastic leukemia (ALL). In this group, chemoresistance may be one of the biggest challenges. An overview of complex cellular processes like drug tolerance can be achieved with proteomic studies. METHODS: The B-lineage pediatric ALL cell line CCRF-SB was gradually exposed to the chemotherapeutic vincristine until proliferation was observed at 6nM, control cells were cultured in the absence of vincristine...
May 2017: Boletín Médico del Hospital Infantil de México
https://www.readbyqxmd.com/read/29367945/cd19-car-t-cells-expressing-il-12-eradicate-lymphoma-in-fully-lymphoreplete-mice-through-induction-of-host-immunity
#19
Gray Kueberuwa, Milena Kalaitsidou, Eleanor Cheadle, Robert Edward Hawkins, David Edward Gilham
Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in cancer therapy. Larger studies have shown ∼90% complete remission rates against chemoresistant and/or refractory CD19+ leukemia or lymphoma. Effective CAR T cell therapy is highly dependent on lymphodepleting preconditioning, which is achieved through chemotherapy or radiotherapy that carries with it significant toxicities. These can exclude patients of low performance status. In order to overcome the need for preconditioning, we constructed fully mouse first and second generation anti-murine CD19 CARs with or without interleukin-12 (IL-12) secretion...
March 30, 2018: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29357914/cell-adhesion-mediated-mitochondria-transfer-contributes-to-mesenchymal-stem-cell-induced-chemoresistance-on-t-cell-acute-lymphoblastic-leukemia-cells
#20
Jiancheng Wang, Xin Liu, Yuan Qiu, Yue Shi, Jianye Cai, Boyan Wang, Xiaoyue Wei, Qiong Ke, Xin Sui, Yi Wang, Yinong Huang, Hongyu Li, Tao Wang, Ren Lin, Qifa Liu, Andy Peng Xiang
BACKGROUND: Despite the high cure rate of T cell acute lymphoblastic leukemia (T-ALL), drug resistance to chemotherapy remains a significant clinical problem. Bone marrow mesenchymal stem cells (MSCs) protect leukemic cells from chemotherapy, but the underlying mechanisms are poorly understood. In this study, we aimed to uncover the mechanism of MSC-induced chemoresistance in T-ALL cells, thus providing a promising clinical therapy target. METHODS: Cell viability was determined using the viability assay kit CCK-8...
January 22, 2018: Journal of Hematology & Oncology
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