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Leukemia chemoresistance

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https://www.readbyqxmd.com/read/29222236/how-and-when-to-decide-between-epigenetic-therapy-and-chemotherapy-in-patients-with-aml
#1
REVIEW
Hervé Dombret, Raphael Itzykson
Remission induction with chemotherapy has long been the frontline treatment of acute myeloid leukemia (AML). However, intensive therapy is limited in frail patients by its associated toxicity and higher rates of failure or relapse in patients with chemoresistant disease, such as secondary AML or poor-risk cytogenetics. Frailty and chemoresistance are more frequent in older adults with AML. In recent years, epigenetic therapies with the hypomethylating agents decitabine and azacitidine have been thoroughly explored in AML...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29208667/etk-interaction-with-pfkfb4-modulates-chemoresistance-of-small-cell-lung-cancer-by-regulating-autophagy
#2
Qiongyao Wang, Fanrui Zeng, Yanqin Sun, Qianqian Qiu, Jian Zhang, Weimei Huang, Jie Huang, Xiaomin Huang, Linlang Guo
PURPOSE: Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx), was found to be critical in modulating the chemoresistance of small cell lung cancer (SCLC) in our preliminary study. However, the molecular mechanisms of Etk in SCLC chemoresistance remain poorly understood. The present study investigated the downstream factor and pathway involved. EXPERIMENTAL DESIGN: We demonstrated first that knockdown of Etk by siRNAs suppressed autophagy in chemoresistant SCLC cells, and that direct inhibition of autophagy sensitized cells to chemotherapy...
December 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
#3
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/29172076/gemtuzumab-ozogamicin-go-inclusion-to-induction-chemotherapy-eliminates-leukemic-initiating-cells-and-significantly-improves-survival-in-mouse-models-of-acute-myeloid-leukemia
#4
Cathy C Zhang, Zhengming Yan, Bernadette Pascual, Amy Jackson-Fisher, Donghui Stephen Huang, Qing Zong, Mark Elliott, Conglin Fan, Nanni Huser, Joseph Lee, Matthew Sung, Puja Sapra
Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-drug conjugate for the treatment of acute myeloid leukemia (AML). Although GO shows a narrow therapeutic window in early clinical studies, recent reports detailing a modified dosing regimen of GO can be safely combined with induction chemotherapy, and the combination provides significant survival benefits in AML patients. Here we tested whether the survival benefits seen with the combination arise from the enhanced reduction of chemoresidual disease and leukemic initiating cells (LICs)...
November 21, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29168399/vacuolar-atpase-as-a-possible-therapeutic-target-in-human-acute-myeloid-leukemia
#5
Elise Aasebø, Sushma Bartaula-Brevik, Maria Hernandez-Valladares, Øystein Bruserud
V-ATPase is a proton pump expressed both in the membrane of intracellular organelles (e.g. endosomes, lysosomes, Golgi structures) and the plasma membrane. It is an important regulator of organellar functions, intracellular molecular trafficking, intercellular communication and intracellular signaling. It is therefore considered as a possible therapeutic target in the treatment of human malignancies. Areas covered: Relevant publications were identified through literature searches in the PubMed database. We searched for original articles and reviews describing the possible importance of V-ATPase for leukemogenesis and chemosensitivity in human myeloid cells, especially acute myeloid leukemia (AML) cells...
November 23, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29164055/micrornas-and-acute-myeloid-leukemia-chemoresistance-a-mechanistic-overview
#6
REVIEW
Martino Marco Gabra, Leonardo Salmena
Up until the early 2000s, a functional role for microRNAs (miRNAs) was yet to be elucidated. With the advent of increasingly high-throughput and precise RNA-sequencing techniques within the last two decades, it has become well established that miRNAs can regulate almost all cellular processes through their ability to post-transcriptionally regulate a majority of protein-coding genes and countless other non-coding genes. In cancer, miRNAs have been demonstrated to play critical roles by modifying or controlling all major hallmarks including cell division, self-renewal, invasion, and DNA damage among others...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/29163809/distinct-signaling-events-promote-resistance-to-mitoxantrone-and-etoposide-in-pediatric-aml-a-children-s-oncology-group-report
#7
Xin Long, Robert B Gerbing, Todd A Alonzo, Michele S Redell
Despite aggressive chemotherapy including mitoxantrone and etoposide, relapse occurs for almost half of children with acute myeloid leukemia (AML). Since both drugs inhibit topoisomerase II and cause DNA double strand breaks, resistance could be achieved by enhanced DNA damage repair (DDR), via homologous recombination (HR) and/or non-homologous end joining (NHEJ). An important source of extrinsic chemoresistance is the bone marrow stroma. We aimed to reveal intrinsic and stroma-induced signaling pathways that contribute to chemoresistance...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29162833/the-combination-of-chk1-inhibitor-with-g-csf-overrides-cytarabine-resistance-in-human-acute-myeloid-leukemia
#8
Alessandro Di Tullio, Kevin Rouault-Pierre, Ander Abarrategi, Syed Mian, William Grey, John Gribben, Aengus Stewart, Elizabeth Blackwood, Dominique Bonnet
Cytarabine (AraC) represents the most effective single agent treatment for AML. Nevertheless, overriding AraC resistance in AML remains an unmet medical need. Here we show that the CHK1 inhibitor (CHK1i) GDC-0575 enhances AraC-mediated killing of AML cells both in vitro and in vivo, thus abrogating any potential chemoresistance mechanisms involving DNA repair. Importantly, this combination of drugs does not affect normal long-term hematopoietic stem/progenitors. Moreover, the addition of CHK1i to AraC does not generate de novo mutations and in patients' samples where AraC is mutagenic, addition of CHK1i appears to eliminate the generation of mutant clones...
November 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/29151814/de-novo-acute-lymphoblastic-leukemia-like-disease-of-high-grade-b-cell-lymphoma-with-myc-and-bcl2-and-or-bcl6-rearrangements-a-case-report-and-literature-review
#9
Akiko Uchida, Yasushi Isobe, Yu Uemura, Yuji Nishio, Hirotaka Sakai, Masayuki Kato, Kaori Otsubo, Masahiro Hoshikawa, Masayuki Takagi, Ikuo Miura
Background: B-cell lymphomas harboring the 8q24/MYC plus 18q21/BCL2 translocations are now referred to as high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-MBR). Although HGBL-MBR is frequently found in cases with diffuse large B-cell lymphoma or Burkitt lymphoma-like B-cell lymphoma, acute lymphoblastic leukemia (ALL)-like disease of HGBL-MBR (AL-HGBL-MBR) has been reported incidentally. Case presentation: A 69-year-old Japanese woman developed remittent fever and increasing systemic bone pain...
2017: BMC Clinical Pathology
https://www.readbyqxmd.com/read/29099494/prognostic-value-of-antigen-expression-in-multiple-myeloma-a-pethema-gem-study-on-1-265-patients-enrolled-in-four-consecutive-clinical-trials
#10
P Arana, B Paiva, M-T Cedena, N Puig, L Cordon, M-B Vidriales, N C Gutierrez, F Chiodi, L Burgos, L-L Anglada, J Martinez-Lopez, M-T Hernandez, A-I Teruel, M Gironella, M-A Echeveste, L Rosiñol, R Martinez, A Oriol, J De la Rubia, A Orfao, J Blade, J-J Lahuerta, M-V Mateos, J F S Miguel
Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Amongst different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly-diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols...
November 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29063676/xiap-inhibition-sensitizes-acute-myeloid-leukemia-cells-response-to-trail-and-chemotherapy-through-potentiated-induction-of-pro-apoptotic-machinery
#11
Jianbiao Zhou, Xiao Lu, Tuan Zea Tan, Wee-Joo Chng
Acute myeloid leukemia (AML) is an aggressive disease with an increasing incidence and relatively low 5-year survival rate. Unfortunately, the underlying mechanism of leukemogenesis is poorly known, and there has been little progress in the treatment for AML. Studies have shown that X-Linked Inhibitor of Apoptosis (XIAP), one of the inhibitor of apoptosis proteins (IAPs), is highly expressed and contributes to chemoresistance in AML. Hence, a novel drug, RO6867520 (abbreviation: RO-BIR2), developed by Roche targeting the BIR2 domain in XIAP to reactivate blocked apoptosis, is a promising therapy for AML...
October 24, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29057300/targeting-atr-chk1-pathway-in-acute-myeloid-leukemia-to-overcome-chemoresistance
#12
Laure David, Stéphane Manenti, Christian Récher, Jean-Sébastien Hoffmann, Christine Didier
Resistance of acute myeloid leukemia to current therapies leads to frequent relapses. Identification of molecular mechanisms involved in chemoresistance constitutes a key challenge to define new therapeutic concepts. Here, we show that the ATR/CHK1 pathway, essential in maintaining genomic stability, is involved in resistance and proliferation characteristics of leukemic cells.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29017371/cytarabine-and-daunorubicin-for-the-treatment-of-acute-myeloid-leukemia
#13
Tracy Murphy, Karen W L Yee
Acute myeloid leukemia (AML) is the most common acute forms of leukemia in adults. It has a poor long-term survival with a high relapse rate and at relapse, is commonly resistant to available therapies. The current combination of daunorubicin (DNR) for three days and cytarabine (Ara-C) as a continuous infusion for seven days, more commonly known as '3 + 7' has remained essentially unaltered over the last forty-four years and remains the standard induction regimen internationally. Areas covered: This paper will briefly review clinically important trials related to '3 + 7'...
October 20, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28939105/protein-kinase-c-eta-regulates-mcl-1-level-via-erk1
#14
Deepanwita Pal, Alakananda Basu
Protein kinase C (PKC)-eta (PKCη) is a member of the novel category of PKC family. It is overexpressed in breast cancer and was shown to inhibit apoptosis and contribute to chemoresistance. Since the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance, we investigated if PKCη regulates Mcl-1 level. Silencing of PKCη decreased Mcl-1 in several breast cancer cells, including MCF-7 and T47D cells. PKCη depletion had no effect on MCL1 mRNA but the decrease in Mcl-1 by PKCη knockdown was blocked by proteasomal inhibitors, such as MG132 and lactacystin...
December 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28923207/eviction-from-the-sanctuary-development-of-targeted-therapy-against-cell-adhesion-molecules-in-acute-lymphoblastic-leukemia
#15
REVIEW
Sonali P Barwe, Anthony Quagliano, Anilkumar Gopalakrishnapillai
Acute lymphoblastic leukemia (ALL) is a malignant hematological disease afflicting hematopoiesis in the bone marrow. While 80%-90% of patients diagnosed with ALL will achieve complete remission at some point during treatment, ALL is associated with high relapse rate, with a 5-year overall survival rate of 68%. The initial remission failure and the high rate of relapse can be attributed to intrinsic chemoprotective mechanisms that allow persistence of ALL cells despite therapy. These mechanisms are mediated, at least in part, through the engagement of cell adhesion molecules (CAMs) within the bone marrow microenvironment...
April 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28917156/tgf%C3%AE-1-synergizes-with-flt3-ligand-to-induce-chemoresistant-quiescence-in-acute-lymphoblastic-leukemia-with-mll-gene-rearrangements
#16
M Tamai, Y Furuichi, S Kasai, N Ando, D Harama, K Goi, T Inukai, K Kagami, M Abe, H Ichikawa, K Sugita
Fms-like tyrosine kinase 3 (FLT3) is highly expressed in mixed-lineage leukemia (MLL) gene-rearranged acute lymphoblastic leukemia (MLL+ALL) with a dismal prognosis. We previously reported that FLT3 ligand (FL) stimulation induced cell cycle arrest in MLL+ALL cells leading to resistance against anti-leukemic agents. Given that FL stimulation enhanced transforming growth factor (TGF)β1 mRNA levels in MLL+ALL cells, we extensively examined the effect of TGFβ1 on the cell cycle progression and chemosensitivity in MLL+ALL cells, and found that TGFβ1 stimulation induced MLL+ALL cells into cell cycle arrest resistant to arabinosyl cytosine; its effect was markedly enhanced in synergy with FL...
October 2017: Leukemia Research
https://www.readbyqxmd.com/read/28881725/nurse-like-cells-promote-cll-survival-through-lfa-3-cd2-interactions
#17
Frédéric Boissard, Marie Tosolini, Laetitia Ligat, Anne Quillet-Mary, Frederic Lopez, Jean-Jacques Fournié, Loic Ysebaert, Mary Poupot
In the tumoral micro-environment (TME) of chronic lymphocytic leukemia (CLL), nurse-like cells (NLC) are tumor-associated macrophages which play a critical role in the survival and chemoresistance of tumoral cells. This pro-survival activity is known to involve soluble factors, but few data are available on the relative role of cells cross-talk. Here, we used a transcriptome-based approach to systematically investigate the expression of various receptor/ligand pairs at the surface of NLC/CLL cells. Their relative contribution to CLL survival was assessed both by fluorescent microscopy to identify cellular interactions and by the use of functional tests to measure the impact of uncoupling these pairs with blocking monoclonal antibodies...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28842696/adhesion-to-stromal-cells-mediates-imatinib-resistance-in-chronic-myeloid-leukemia-through-erk-and-bmp-signaling-pathways
#18
Atul Kumar, Jina Bhattacharyya, Bithiah Grace Jaganathan
Chronic myeloid leukemia (CML) is characterized by abnormal proliferation of myeloid cells which when untreated leads to bone marrow failure. Imatinib mesylate (IM) is the first line of therapy for treatment of CML and results in remission in most cases. However, a significant percentage of patients develop chemoresistance to IM, which might be due to the presence of chemoresistant cells in the bone marrow. In the current study, we explored the role of cell-cell interaction of CML cells with the bone marrow stromal cells in the development of chemoresistance in CML...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28807161/phytochemical-modulation-of-apoptosis-and-autophagy-strategies-to-overcome-chemoresistance-in-leukemic-stem-cells-in-the-bone-marrow-microenvironment
#19
Helen C Owen, Sandra Appiah, Noor Hasan, Lucy Ghali, Ghada Elayat, Celia Bell
Advances in scientific research and targeted treatment regimes have improved survival rates for many cancers over the past few decades. However, for some types of leukemia, including acute lymphoblastic and acute myeloid leukemia, mortality rates have continued to rise, with chemoresistance in leukemic stem cells (LSCs) being a major contributing factor. Most cancer drug therapies act by inducing apoptosis in dividing cells but are ineffective in targeting quiescent LSCs. Niches in the bone marrow, known as leukemic niches, behave as "sanctuaries" where LSCs acquire drug resistance...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28775123/toll-like-receptor-9-stimulation-can-induce-i%C3%AE%C2%BAb%C3%AE-expression-and-igm-secretion-in-chronic-lymphocytic-leukemia-cells
#20
Eleonora Fonte, Maria Giovanna Vilia, Daniele Reverberi, Ilenia Sana, Lydia Scarfò, Pamela Ranghetti, Ugo Orfanelli, Simone Cenci, Giovanna Cutrona, Paolo Ghia, Marta Muzio
Chronic lymphocytic leukemia cells strongly depend on external stimuli for their survival. Both antigen receptor and co-stimulatory receptors, including Toll-like receptors, can modulate viability and proliferation of leukemic cells. Toll-like receptor ligands, and particularly the TLR9 ligand CpG, mediate heterogeneous responses in patients' samples reflecting the clinical course of the subjects. However, the molecular framework of the key signaling events underlying such heterogeneity is undefined. We focused our studies on a subset of chronic lymphocytic leukemia cases characterized by expression of CD38 and unmutated immunoglobulin genes, who respond to CpG with enhanced metabolic cell activity...
November 2017: Haematologica
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