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Leukemia chemoresistance

Aleš Hnízda, Jana Škerlová, Milan Fábry, Petr Pachl, Martina Šinalová, Lukáš Vrzal, Petr Man, Petr Novák, Pavlína Řezáčová, Václav Veverka
BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) is one of the main causes of mortality in childhood malignancies. Previous genetic studies demonstrated that chemoresistant ALL is driven by activating mutations in NT5C2, the gene encoding cytosolic 5´-nucleotidase (cN-II). However, molecular mechanisms underlying this hyperactivation are still unknown. Here, we present kinetic and structural properties of cN-II variants that represent 75 % of mutated alleles in patients who experience relapsed ALL (R367Q, R238W and L375F)...
October 19, 2016: BMC Biology
Tian Fang, Hongwei Lv, Fuquan Wu, Changzheng Wang, Ting Li, Guishuai Lv, Liang Tang, Linna Guo, Shanhua Tang, Dan Cao, Mengchao Wu, Wen Yang, Hongyang Wang
Accumulating evidence suggests that cancer stem cells (CSCs), a small subset of cancer cells, are responsible for tumor initiation, progression, relapse and metastasis. Musashi 2 (MSI2), a RNA-binding protein, was proposed to be a potent oncogene playing key roles in myeloid leukemia and gastrointestinal malignancies. However, it remains elusive how MSI2 regulates stem cell features in HCC. Herein, we demonstrated that MSI2 was highly expressed in liver CSCs. Overexpression or knockdown of MSI2 altered CSC-related gene expression, self-renewal as well as resistance to chemotherapy in HCC cell lines...
October 6, 2016: Cancer Letters
Juan Han, Runming Jin, Meiling Zhang, Qing Guo, Fen Zhou
Ikaros isoform 6 (Ik6) is associated with a poor prognosis for children with acute lymphoblastic leukemia (ALL). Our previous study demonstrated that overexpression of Ik6 enhances proliferation and chemoresistance of leukemia cells, with a possible underlying mechanism that involves antiapoptosis. In the present study, we investigated whether Ik6 protects against apoptosis by regulating the Akt-FoxO1 pathway. Bone marrow samples from children with ALL were collected and evaluated. In Ik6(+) patients, the Akt-FoxO1 pathway was activated such that expression of phosphorylated Akt and FoxO1 was significantly increased, but that of Bim and p27 decreased...
October 5, 2016: Journal of Leukocyte Biology
Xiaohu Zheng, Xiaolei Fan, Binqing Fu, Meijuan Zheng, Aimei Zhang, Kai Zhong, Jialai Yan, Rui Sun, Zhigang Tian, Haiming Wei
The lack of effective tumor-associated antigens restricts the development of targeted therapies against myeloid leukemia. In this study, we compared gene expression patterns of acute myeloid leukemia (AML) and normal bone marrow samples and found that epithelial cell adhesion molecule (EpCAM) is frequently overexpressed in patients with AML, with EpCAM+ leukemic cells exhibiting enhanced chemoresistance and oncogenesis. The chemotherapeutic resistance of EpCAM-positive leukemic cells is a consequence of increased WNT5B signaling...
October 3, 2016: Cancer Research
I Khan, M Halasi, M F Zia, P Gann, S Gaitonde, N Mahmud, A L Gartel
Leukemia accepted article preview online, 03 October 2016. doi:10.1038/leu.2016.270.
October 3, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Lu Qian, Wanggang Zhang, Bo Lei, Aili He, Lianhong Ye, Xingzhou Li, Xin Dong
The present study aimed to investigate the role of microRNA (miR)-101 in acute lymphoblastic leukemia progression and chemoresistance. Furthermore, a novel target gene of miR-101 was identified. Here, we confirmed that miR-101 was significantly downregulated in the blood samples of patients with T-cell acute lymphoblastic leukemia (T-ALL) compared with the healthy controls, as determined by reverse transcription quantitative polymerase chain reaction (RTqPCR) analysis. The in vitro experiments demonstrated that miR-101 significantly repressed the proliferation and invasion, and induced potent apoptosis in Jurkat cells, as determined by CCK-8, flow cytometer and cell invasion assays...
September 21, 2016: Oncology Reports
M H Shahi, S Farheen, M P M Mariyath, J S Castresana
Chemoresistance is a common hurdle for the proper treatment of gliomas. The role of Shh-Gli1 signaling in glioma progression has been reported. However, its role in glioma chemoresistance has not been well studied yet. In this work, we found that Shh-Gli1 signaling regulates the expression of one stem cell marker, BMI1 (B cell-specific Moloney murine leukemia virus), in glioma. Interestingly, we also demonstrated high expression of MRP1 (multi-drug resistance protein 1) in glioma. MRP1 expression was decreased by BMI1 siRNA and Shh-Gli1 cell signaling specific inhibitor GANT61 in our experiments...
September 23, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
C Petit, F Gouel, I Dubus, C Heuclin, K Roget, J P Vannier
BACKGROUND: Several studies show that bone marrow (BM) microenvironment and hypoxia condition can promote the survival of leukemic cells and induce resistance to anti-leukemic drugs. However, the molecular mechanism for chemoresistance by hypoxia is not fully understood. METHODS: In the present study, we investigated the effect of hypoxia on resistance to two therapies, methotrexate (MTX) and prednisolone (PRD), in two cell models for acute lymphoblastic leukemia (ALL)...
2016: BMC Cancer
Jie Lei, Qi Li, Ying Gao, Lei Zhao, Yanbo Liu
Chemoresistant mechanisms in T-cell acute lymphoblastic leukemia (T-ALL) patients are not clarified. The apoptotic signaling mediated by receptor of activated C kinase 1 (Rack1), protein kinase C (PKC) and FEM1 homolog b (FEM1b) was investigated in two T-ALL-derived cell lines (Jurkat and CCRF-CEM) following treatment with chemotherapy drugs vincristine and prednisone. Serum starvation or chemotherapeutic drugs significantly reduced Rack1 level and PKC activation, while promoted cellular apoptosis in both cell lines...
2016: Scientific Reports
Laure David, Anne Fernandez-Vidal, Sarah Bertoli, Srdana Grgurevic, Benoît Lepage, Dominique Deshaies, Naïs Prade, Maëlle Cartel, Clément Larrue, Jean-Emmanuel Sarry, Eric Delabesse, Christophe Cazaux, Christine Didier, Christian Récher, Stéphane Manenti, Jean-Sébastien Hoffmann
The nucleoside analog cytarabine, an inhibitor of DNA replication fork progression that results in DNA damage, is currently used in the treatment of acute myeloid leukemia (AML). We explored the prognostic value of the expression of 72 genes involved in various aspects of DNA replication in a set of 198 AML patients treated by cytarabine-based chemotherapy. We unveiled that high expression of the DNA replication checkpoint gene CHEK1 is a prognostic marker associated with shorter overall, event-free, and relapse-free survivals and determined that the expression of CHEK1 can predict more frequent and earlier postremission relapse...
2016: Science Signaling
Kelly M Arcipowski, Marinka Bulic, Sandeep Gurbuxani, Jonathan D Licht
Two of the most common myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), are associated with exceedingly low survival rates despite recent therapeutic advances. While their etiology is not completely understood, evidence suggests that certain chromosomal abnormalities contribute to MDS and AML progression. Among the most frequent chromosomal abnormalities in these disorders are alterations of chromosome 7: either complete loss of one copy of chromosome 7 (-7) or partial deletion of 7q (del(7q)), both of which increase the risk of progression from MDS to AML and are associated with chemoresistance...
2016: PloS One
Patrick D Bhola, Brenton G Mar, R Coleman Lindsley, Jeremy A Ryan, Leah J Hogdal, Thanh Trang Vo, Daniel J DeAngelo, Ilene Galinsky, Benjamin L Ebert, Anthony Letai
Upfront resistance to chemotherapy and relapse following remission are critical problems in leukemia that are generally attributed to subpopulations of chemoresistant tumor cells. There are, however, limited means for prospectively identifying these subpopulations, which hinders an understanding of therapeutic resistance. BH3 profiling is a functional single-cell analysis using synthetic BCL-2 BH3 domain-like peptides that measures mitochondrial apoptotic sensitivity or "priming." Here, we observed that the extent of apoptotic priming is heterogeneous within multiple cancer cell lines and is not the result of experimental noise...
October 3, 2016: Journal of Clinical Investigation
Tsui-Ting Ho, Xiaolong He, Yin-Yuan Mo, William T Beck
The acquisition of resistance to anticancer drugs is widely viewed as a key obstacle to successful cancer therapy. However, detailed knowledge of the initial molecular events in the response of cancer cells to these chemotherapeutic and stress responses, and how these lead to the development of chemoresistance, remains incompletely understood. Using microRNA array and washout and rechallenge experiments, we found that short term treatment of leukemia cells with etoposide led a few days later to transient resistance that was associated with a corresponding transient increase in expression of ABCB1 mRNA, as well as microRNA (miR)-135b and miR-196b...
2016: International Journal of Biochemistry and Molecular Biology
Xiao-Yan Yang, Ming-Ying Zhang, Qi Zhou, Shui-Yan Wu, Ye Zhao, Wei-Ying Gu, Jian Pan, Jian-Nong Cen, Zi-Xing Chen, Wen-Ge Guo, Chien-Shing Chen, Wen-Hua Yan, Shao-Yan Hu
S100A8 has been increasingly recognized as a biomarker in multiple solid tumors and has played pivotal roles in hematological malignancies. S100A8 is potentially an indicator for poor survival in acute myeloid leukemia (AML) in retrospective studies. However, the mechanisms of S100A8 are diverse in cancers. In this study, we investigated the correlation of S100A8 at the transcription level with clinical parameters in 91 de novo AML patients and explored its mechanisms of chemoresistance to etoposide in vitro...
2016: OncoTargets and Therapy
Lifen Zhao, Yan Li, Xiaobo Song, Huimin Zhou, Nana Li, Yuan Miao, Li Jia
Chemotherapy resistance frequently drives tumor progression. Increased expression of ST8SIA4 has been reported in diverse carcinomas and highly correlates with leukemia multidrug resistance (MDR). MicroRNAs (miRNA) are widely recognized as key players in cancer progression and drug resistance. Here, to explore whether miRNA modulates the sensitivity of chronic myelocytic leukemia (CML) to chemotherapeutic agents and regulates ST8SIA4 expression, we analyzed the complete miRNA expression profile and found a subset of miRNAs specifically dysregulated in adriamycin-resistant CML cell line K562/ADR and its parent cell line K562...
August 4, 2016: Oncotarget
Nicholas J Short, Farhad Ravandi
Dose intensification of chemotherapy and the combination of a third cytotoxic agent with standard cytarabine and anthracycline-based induction chemotherapy have led to improved outcomes in select groups of patients with acute myeloid leukemia (AML). However, despite some progress in this area, it appears that we might be reaching the limit of cytotoxic chemotherapy for the treatment of AML, especially in older patients and in those with poor-risk features whose disease tends to be relatively chemoresistant...
August 2016: Clinical Lymphoma, Myeloma & Leukemia
Yi Liao, Xiaojia Niu, Bailing Chen, Holly Edwards, Liping Xu, Chengzhi Xie, Hai Lin, Lisa Polin, Jeffrey W Taub, Yubin Ge, Zhihui Qin
Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1-58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells. Both PL and HDACi components, either in combination or in hybrid molecules, are essential for inducing significant DNA damage and apoptosis. Introducing C2-chloro substituent to 1-58 yielded 3-35 with increased cytotoxicity but decreased selectivity in noncancerous MCF-10A cells; eliminating C7-C8 olefin of PL obtained 3-31/3-98 scaffolds which were still more active than PL or SAHA in AML and were well-tolerated by MCF-10A cells...
September 8, 2016: Journal of Medicinal Chemistry
B Paiva, N Puig, M T Cedena, B G de Jong, Y Ruiz, I Rapado, J Martinez-Lopez, L Cordon, D Alignani, J A Delgado, M C van Zelm, J J M Van Dongen, M Pascual, X Agirre, F Prosper, J I Martín-Subero, M-B Vidriales, N C Gutierrez, M T Hernandez, A Oriol, M A Echeveste, Y Gonzalez, S K Johnson, J Epstein, B Barlogie, G J Morgan, A Orfao, J Blade, M V Mateos, J J Lahuerta, J F San-Miguel
The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs...
September 16, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Hasita Horlad, Koji Ohnishi, Chaoya Ma, Yukio Fujiwara, Daisuke Niino, Koichi Ohshima, Masahisa Jinushi, Masao Matsuoka, Motohiro Takeya, Yoshihiro Komohara
Adult T-cell leukemia/lymphoma (ATLL), an aggressive type of malignant lymphoma, is highly resistant to chemotherapy. However, the detailed mechanisms of the chemoresistance of ATLL have never been elucidated. We previously demonstrated that direct cell-cell interaction between macrophages and lymphoma cells was significantly associated with lymphoma progression in patients with ATLL. The present study aimed to further analyze the effects of cell-cell interaction between macrophages and ATLL cells by means of cell culture studies and immunohistochemical analysis using human ATLL samples...
August 2016: Oncology Letters
Rachana Trivedi, Gerhard A Müller, Manohar S Rathore, Durga P Mishra, Hassan Dihazi
BACKGROUND/AIMS: ER-Stress and activation of unfolded protein response belong to the major factors involved in chemoresistance in cancer cells. In this study we investigated the effect of shikonin on the survival of acute myeloid leukemia cells and the role of ER-stress protein ERP57, a protein disulfide isomerase, in improvement of chemotherapy. METHODS: Using MTT assay we studied cytotoxic effects of shikonin on HL-60 cells. The flow cytometry was adopted to examine the shikonin induced mode of cell death in HL-60 cells...
2016: Cellular Physiology and Biochemistry
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