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https://www.readbyqxmd.com/read/29147589/%C3%AE-%C3%AE-t-cell-acute-lymphoblastic-leukemia-lymphoma-discussion-of-two-pediatric-cases-and-its-distinction-from-other-mature-%C3%AE-%C3%AE-t-cell-malignancies
#1
Eric X Wei, Vasiliki Leventaki, John K Choi, Susana C Raimondi, Elizabeth M Azzato, Sheila A Shurtleff, Menchu G Ong, Diana M Veillon, James D Cotelingam, Rodney E Shackelford
Gamma delta (γδ) T-cell antigen receptor (TCR) expression and its related T-cell differentiation are not commonly reported in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Here we report two pediatric T-ALL cases and present their clinical features, histology, immunophenotypes, cytogenetics, and molecular diagnostic findings. The first patient is a two-year-old girl with leukocytosis, circulating lymphoblasts, and a cryptic insertion of a short-arm segment at 10p12 into the long-arm segment of 11q23 resulting in an MLL and AF10 fusion transcript, which may be the first reported in γδ T-ALL...
2017: Case Reports in Hematology
https://www.readbyqxmd.com/read/29142068/pharmacologic-inhibition-of-the-menin-mll-interaction-leads-to-transcriptional-repression-of-peg10-and-blocks-hepatocellular-carcinoma
#2
Katarzyna Kempinska, Bhavna Malik, Dmitry Borkin, Szymon Klossowski, Shirish Shukla, Hongzhi Miao, Jingya Wang, Tomasz Cierpicki, Jolanta Grembecka
Hepatocellular carcinoma (HCC) accounts for ~85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein-protein interaction between menin and histone methyltransferase Mixed Lineage Leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients...
November 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29137234/the-af4-mll-fusion-transiently-augments-multilineage-hematopoietic-engraftment-but-is-not-sufficient-to-initiate-leukemia-in-cord-blood-cd34-cells
#3
Cristina Prieto, Rolf Marschalek, Alessa Kühn, Adelheid Bursen, Clara Bueno, Pablo Menéndez
The translocation t(4;11)(q21;q23) is the hallmark genetic abnormality associated with infant pro-B acute lymphoblastic leukemia (B-ALL) and has the highest frequency of rearrangement in Mixed-lineage leukemia (MLL) leukemias. Unlike other MLL translocations, MLL-AF4-induced proB-ALL is exceptionally difficult to model in mice/humans. Previous work has investigated the relevance of the reciprocal translocation fusion protein AF4-MLL for t(4;11) leukemia, finding that AF4-MLL is capable of inducing proB-ALL without requirement for MLL-AF4 when expressed in murine hematopoietic stem/progenitor cells (HSPCs)...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29133595/targeted-next-gen-sequencing-for-detecting-mll-gene-fusions-in-leukemia
#4
Sadia Afrin, Christine Rc Zhang, Claus Meyer, Caedyn L Stinson, Thy Pham, Timothy Jc Bruxner, Nicola C Venn, Toby N Trahair, Rosemary Sutton, Rolf Marschalek, J Lynn Fink, Andrew S Moore
Mixed Lineage Leukemia (MLL) gene rearrangements characterize approximately 70% of infant and 10% of adult and therapy-related leukemia. Conventional clinical diagnostics, including cytogenetics and fluorescence in situ hybridization (FISH) fail to detect MLL translocation partner genes (TPGs) in many patients. Long-Distance Inverse (LDI)-PCR, the 'gold standard' technique that is used to characterize MLL breakpoints is laborious and requires a large input of genomic DNA (gDNA). To overcome the limitations of current techniques, a targeted Next-Generation Sequencing (NGS) approach that requires low RNA input was tested...
November 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29127121/pkc-epsilon-is-a-key-regulator-of-mitochondrial-redox-homeostasis-in-acute-myeloid-leukemia
#5
Daniela Di Marcantonio, Esteban Martinez, Simone Sidoli, Jessica Vadaketh, Margaret Nieborowska-Skorska, Anushk Gupta, Jacob Michael Meadows, Francesca Ferraro, Elena Masselli, Grant A Challen, Michael D Milsom, Claudia Scholl, Stefan Froehling, Siddharth Balachandran, Tomasz Skorski, Benjamin Garcia, Prisco Mirandola, Giuliana Gobbi, Ramiro Garzon, Marco Vitale, Stephen M Sykes
PURPOSE: The intracellular redox environment of acute myeloid leukemia (AML) cells is often highly oxidized compared to healthy hematopoietic progenitors and this is purported to contribute to disease pathogenesis. However, the redox regulators that allow AML cell survival in this oxidized environment remain largely unknown. EXPERIMENTAL DESIGN AND RESULTS: We show that RNA interference-mediated inhibition of the serine/threonine kinase PKC-epsilon (PKCe) reduces cell survival in a diverse panel of patient-derived AML samples and significantly delays disease onset in a genetically engineered mouse model (GEMM) of AML driven by MLL-AF9...
November 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29109446/bruton-s-tyrosine-kinase-and-rac1-promote-cell-survival-in-mll-rearranged-acute-myeloid-leukemia
#6
S C Nimmagadda, S Frey, B Edelmann, C Hellmich, L Zaitseva, G M König, E Kostenis, K M Bowles, T Fischer
Leukemia accepted article preview online, 07 November 2017. doi:10.1038/leu.2017.324.
November 7, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29105243/performance-of-multiplex-fusion-gene-testing-in-pediatric-acute-myeloid-leukemia
#7
Yuka Iijima-Yamashita, Hidemasa Matsuo, Miho Yamada, Takao Deguchi, Nobutaka Kiyokawa, Akira Shimada, Akio Tawa, Hiroyuki Takahashi, Daisuke Tomizawa, Takashi Taga, Akitoshi Kinoshita, Souichi Adachi, Keizo Horibe
BACKGROUND: Gene abnormalities, particularly chromosome rearrangements generating gene fusions, are associated with clinical characteristics and prognosis in pediatric acute myeloid leukemia (AML). Karyotyping is generally performed to enable risk stratification; however, the results are not always consistent with those generated by reverse transcription-polymerase chain reaction (RT-PCR), and more accurate and rapid methods are required. METHODS: A total of 487 samples from de novo AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (n = 448), and acute promyelocytic leukemia (APL) patients enrolled in the JPLSG AML-P05 study (n = 39) were available for this investigation...
November 4, 2017: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/29089643/targeting-acute-myeloid-leukemia-by-drug-induced-c-myb-degradation
#8
V Walf-Vorderwülbecke, K Pearce, T Brooks, M Hubank, M M van den Heuvel-Eibrink, C M Zwaan, S Adams, D Edwards, J Bartram, S Samarasinghe, P Ancliff, A Khwaja, N Goulden, G Williams, J de Boer, O Williams
Despite advances in our understanding of the molecular basis for particular subtypes of acute myeloid leukemia (AML), effective therapy remains a challenge for many individuals suffering from this disease. A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. The transcription factor c-MYB has been shown to play a central role in the development and progression of AML driven by several different oncogenes, including mixed lineage leukemia (MLL)-fusion genes...
November 1, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29075615/pharmacologic-targeting-of-chromatin-modulators-as-therapeutics-of-acute-myeloid-leukemia
#9
REVIEW
Rui Lu, Gang Greg Wang
Acute myeloid leukemia (AML), a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently "hit" genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/29073272/highly-aggressive-rat-prostate-tumors-rapidly-precondition-regional-lymph-nodes-for-subsequent-metastatic-growth
#10
Kerstin Strömvall, Marie Lundholm, Elin Thysell, Anders Bergh, Sofia Halin Bergström
The aim of this study was to examine in what ways MatLyLu (MLL) rat prostate tumors with high metastatic capacity influence regional lymph nodes prior to metastatic establishment compared to AT1 rat prostate tumors with low metastatic potential. MLL or AT1 tumor cells were injected into the ventral prostate of immunocompetent rats. Tumor and lymph node morphology, and lymph node mRNA expression of macrophage associated markers, T-cell associated markers, and cytokines were examined over time until the first microscopic signs of metastases (at day 14 for MLL- and at day 28 for AT1-tumors)...
2017: PloS One
https://www.readbyqxmd.com/read/29070104/-effects-of-dot1l-inhibitor-epz-5676-combined-with-chemotherapeutic-drugs-on-prolifiration-and-apoptosis-of-rs-4-11-cells
#11
Li-Hong Li, Jing Wang, Xiao-Yan Ke
OBJECTIVE: To investigate the synergistic antiproliferative and inducing-apoptotic effect of EPZ-5676 combined with chemotherapeutic drugs on acute lymploblastic leukemia(ALL). METHODS: The MLL rearragement positive (MLL-r(+)) ALL cell line RS4;11 was treated with EPZ-5676 alone and its combination with 5 kinds of chemotherapeutic drugs of ALL, the CCK-8 method was used to assay the inhibitory rate of leukemia cells treated with EPZ-5676 and chemotherapeutic drugs alone and their combination; the compusyn software was used to evaluate the relationthip between inhibitory rate (Fa) of combined drugs for leukemia cells and combination index (CI), and to determine the interaction of drugs; the flow cytometry with Annexin V-FITC/PI double staining was used to detect the apoptotic rate of RS4;11 treated EPZ-5676, GC, VCR, CTX, epirubicin and VP16 alone and combination of EPZ-5676 with them and to compare the inducing apoptotic effect of combined drugs...
October 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29069784/high-expression-of-dedicator-of-cytokinesis-1-dock1-confers-poor-prognosis-in-acute-myeloid-leukemia
#12
Sze-Hwei Lee, Yu-Chiao Chiu, Yi-Hung Li, Chien-Chin Lin, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien
DOCK family genes encode evolutionarily conserved guanine nucleotide exchange factors for Rho GTPase involving multiple biological functions. Yet the patterns and prognostic significance of their expression in acute myeloid leukemia (AML) remain unexplored. Here we analyzed the expression patterns of 11 DOCK family genes in AML cells based on the array data of 347 patients from our cohort and several other published datasets. We further focused on the implications of the expression of DOCK1 since it was the only one in DOCK family to be associated with survival...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29067751/monitoring-of-fusion-gene-transcripts-to-predict-relapses-in-pediatric-acute-myeloid-leukemia
#13
Hidemasa Matsuo, Yuka Iijima-Yamashita, Miho Yamada, Takao Deguchi, Nobutaka Kiyokawa, Akira Shimada, Akio Tawa, Daisuke Tomizawa, Takashi Taga, Akitoshi Kinoshita, Souichi Adachi, Keizo Horibe
BACKGROUND: In acute myeloid leukemia (AML), accurate detection of minimal residual disease (MRD) enables better risk-stratified therapy. However, there are few studies monitoring multiple fusion transcripts and evaluating their accuracy as MRDs at multiple timepoints. METHODS: We retrospectively examined RNA obtained from 82 pediatric AML patients enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. The expression of six important fusion transcripts (AML1(RUNX1)-ETO, CBFB-MYH11, MLL(KMT2A)-AF9, MLL-ELL, MLL-AF6, and FUS-ERG) was analyzed at five timepoints 30-40 days apart following diagnosis...
October 25, 2017: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/29062045/evolution-of-af6-ras-association-and-its-implications-in-mixed-lineage-leukemia
#14
Matthew J Smith, Elizabeth Ottoni, Noboru Ishiyama, Marilyn Goudreault, André Haman, Claus Meyer, Monika Tucholska, Genevieve Gasmi-Seabrook, Serena Menezes, Rob C Laister, Mark D Minden, Rolf Marschalek, Anne-Claude Gingras, Trang Hoang, Mitsuhiko Ikura
Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization...
October 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/29056538/the-role-of-ras-mutations-in-mll-rearranged-leukaemia-a-path-to-intervention
#15
REVIEW
Marcela B Mansur, Anthony M Ford, Mariana Emerenciano
Childhood acute lymphoblastic leukaemia (ALL) with MLL rearrangement (MLL-r) is an aggressive disease still associated with a high mortality rate. Recent investigations have identified co-operating mutations in the RAS pathway and although the functional consequences of these mutations are not yet fully understood, aberrant regulation of RAS pathway signalling at both transcriptional and protein levels is observed. Studies investigating the efficacy of specific inhibitors of this pathway, e.g. MEK-inhibitors, have also achieved encouraging results...
October 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29052026/high-dose-chemotherapy-and-autologous-peripheral-blood-stem-cell-transplantation-with-bcvac-regimen-followed-by-maintenance-chemotherapy-for-children-with-very-high-risk-acute-lymphoblastic-leukemia
#16
Che Ry Hong, Hyoung Jin Kang, Kyung Duk Park, Hee Young Shin, Hyo Seop Ahn
Allogeneic hematopoietic stem cell transplantation (HSCT) is the recommended treatment for children with very high risk acute lymphoblastic leukemia (ALL), but it requires adequate institutional infrastructure, experience, and expertise, especially for alternative donor HSCT. We review our experience with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (APBSCT), followed by post-APBSCT maintenance chemotherapy for children with very high risk ALL. Between August 1997 and November 2012, our institute was not successful with HLA-haploidentical HSCT...
October 20, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/29043883/structural-maintenance-of-chromosomes-4-is-required-for-leukemia-stem-cell-maintenance-in-mll-af9-induced-acute-myeloid-leukemia
#17
Luyun Peng, Yuanting Tang, Yingchi Zhang, Siqi Guo, Leiwen Peng, Lei Ye, Yuefang Wang, Yongmei Jiang
The gene, structural maintenance of chromosomes 4 (SMC4) plays important role in chromosomes condensing and mitotic sister chromatid segregation, which has been revealed in regulating multiple cancer development and carcinogenesis. However, the role of SMC4 in acute myeloid leukemia (AML) propagation and its function in regulation of leukemia stem cells (LSCs) is not yet clear. Using an MLL-AF9 induced AML mouse model, we demonstrated that down modulating of SMC4 expression could prolong the survival time of AML mice...
October 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29042647/ultrasensitive-high-dynamic-range-and-broadband-strain-sensing-by-time-of-flight-detection-with-femtosecond-laser-frequency-combs
#18
Xing Lu, Shuangyou Zhang, Xing Chen, Dohyeon Kwon, Chan-Gi Jeon, Zhigang Zhang, Jungwon Kim, Kebin Shi
Ultrahigh-resolution optical strain sensors provide powerful tools in various scientific and engineering fields, ranging from long-baseline interferometers to civil and aerospace industries. Here we demonstrate an ultrahigh-resolution fibre strain sensing method by directly detecting the time-of-flight (TOF) change of the optical pulse train generated from a free-running passively mode-locked laser (MLL) frequency comb. We achieved a local strain resolution of 18 pε/Hz(1/2) and 1.9 pε/Hz(1/2) at 1 Hz and 3 kHz, respectively, with large dynamic range of >154 dB at 3 kHz...
October 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29027108/prognostic-value-of-genetic-mutations-in-adolescent-and-young-adults-with-acute-myeloid-leukemia
#19
Yachiyo Kuwatsuka, Daisuke Tomizawa, Rika Kihara, Yasunobu Nagata, Norio Shiba, Yuka Iijima-Yamashita, Akira Shimada, Takao Deguchi, Hayato Miyachi, Akio Tawa, Takashi Taga, Akitoshi Kinoshita, Hideki Nakayama, Nobutaka Kiyokawa, Akiko Moriya Saito, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Norio Asou, Shigeki Ohtake, Shuichi Miyawaki, Yasushi Miyazaki, Toru Sakura, Yukiyasu Ozawa, Noriko Usui, Heiwa Kanamori, Yoshikazu Ito, Kiyotoshi Imai, Youko Suehiro, Shinichi Kobayashi, Kunio Kitamura, Emiko Sakaida, Seishi Ogawa, Tomoki Naoe, Yasuhide Hayashi, Keizo Horibe, Atsushi Manabe, Shuki Mizutani, Souichi Adachi, Hitoshi Kiyoi
Clinical outcomes and the genetic background of acute myeloid leukemia (AML) in adolescent and young adults (AYAs) are known to differ in younger children and older adults. To clarify the impact of genetic mutations on clinical outcomes of AYAs with AML, we analyzed data from the JPLSG AML-05 and JALSG AML201 studies. AYAs aged 15-39 years (n = 103) were included. FLT3-ITD, KIT, CEBPA, NRAS, KRAS, WT1, MLL-PTD, and NPM1 mutations were analyzed. Overall survival (OS) of the AYAs was 61% and event-free survival was 38% at 3 years...
October 12, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/29019697/development-of-potent-type-i-protein-arginine-methyltransferase-prmt-inhibitors-of-leukemia-cell-proliferation
#20
Chen Wang, Hao Jiang, Jia Jin, Yiqian Xie, Zhifeng Chen, Hao Zhang, Fulin Lian, Yu-Chih Liu, Chenhua Zhang, Hong Ding, Shijie Chen, Naixia Zhang, Yuanyuan Zhang, Hualiang Jiang, Kaixian Chen, Fei Ye, Zhiyi Yao, Cheng Luo
Protein Arginine Methyltransferases (PRMTs) are crucial players in diverse biological processes, and dysregulation of PRMTs has been linked to various human diseases, especially cancer. Therefore, small molecules targeting PRMTs have profound impact for both academic functional studies and clinical disease treatment. Here, we report the discovery of N(1)-(2-((2-chlorophenyl)thio)benzyl)-N(1)-methylethane-1,2-diamine (28d, DCPR049_12), a highly potent inhibitor of type I PRMTs that has good selectivity against a panel of other methyltransferases...
October 27, 2017: Journal of Medicinal Chemistry
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