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https://www.readbyqxmd.com/read/29351983/partial-tandem-duplication-of-kmt2a-mll-may-predict-a-subset-of-myelodysplastic-syndrome-with-unique-characteristics-and-poor-outcome
#1
Sarah M Choi, Rajan Dewar, Patrick W Burke, Lina Shao
Partial tandem duplication (PTD) of the KMT2A (MLL) gene is a poor prognostic factor in acute myeloid leukemia, but its significance in the context of myelodysplastic syndrome (MDS) is unknown. Here, we used cytogenomic array to identify MLL-PTD in a group of MDS patients and compared their clinicopathologic characteristics with a cohort of high-risk MDS patients without MLL-PTD. We show that MLL-PTD defines a subset of MDS characterized by high blast count, normal karyotype, and extremely poor prognosis exceeding that of non-MLL-PTD high risk MDS, including those with complex karyotype...
January 19, 2018: Haematologica
https://www.readbyqxmd.com/read/29343972/targeting-histone-methyltransferase-and-demethylase-in-acute-myeloid-leukemia-therapy
#2
REVIEW
Germana Castelli, Elvira Pelosi, Ugo Testa
Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and clinical heterogeneity. Advances in genomic technologies have increasingly shown the complexity and heterogeneity of genetic and epigenetic alterations in AML. Among the genetic alterations occurring in AML, frequent are the genetic alterations at the level of various genes involved in the epigenetic control of the DNA methylome and histone methylome...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29343685/the-protective-role-of-dot1l-in-uv-induced-melanomagenesis
#3
Bo Zhu, Shuyang Chen, Hongshen Wang, Chengqian Yin, Changpeng Han, Cong Peng, Zhaoqian Liu, Lixin Wan, Xiaoyang Zhang, Jie Zhang, Christine G Lian, Peilin Ma, Zhi-Xiang Xu, Sharon Prince, Tao Wang, Xiumei Gao, Yujiang Shi, Dali Liu, Min Liu, Wenyi Wei, Zhi Wei, Jingxuan Pan, Yongjun Wang, Zhenyu Xuan, Jay Hess, Nicholas K Hayward, Colin R Goding, Xiang Chen, Jun Zhou, Rutao Cui
The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation...
January 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29342133/a-myc-enhancer-cluster-regulates-normal-and-leukaemic-haematopoietic-stem-cell-hierarchies
#4
Carsten Bahr, Lisa von Paleske, Veli V Uslu, Silvia Remeseiro, Naoya Takayama, Stanley W Ng, Alex Murison, Katja Langenfeld, Massimo Petretich, Roberta Scognamiglio, Petra Zeisberger, Amelie S Benk, Ido Amit, Peter W Zandstra, Mathieu Lupien, John E Dick, Andreas Trumpp, François Spitz
The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a 'super-enhancer' is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29335872/disruptor-of-telomeric-silencing-1-like-dot1l-disclosing-a-new-class-of-non-nucleoside-inhibitors-by-means-of-ligand-based-and-structure-based-approaches
#5
Manuela Sabatino, Dante Rotili, Alexandros Patsilinakos, Mariantonietta Forgione, Daniela Tomaselli, Fréderic Alby, Paola B Arimondo, Antonello Mai, Rino Ragno
Chemical inhibition of chromatin-mediated signaling involved proteins is an established strategy to drive expression networks and alter disease progression. Protein methyltransferases are among the most studied proteins in epigenetics and, in particular, disruptor of telomeric silencing 1-like (DOT1L) lysine methyltransferase plays a key role in MLL-rearranged acute leukemia Selective inhibition of DOT1L is an established attractive strategy to breakdown aberrant H3K79 methylation and thus overexpression of leukemia genes, and leukemogenesis...
January 15, 2018: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29320732/stabilization-of-nf-%C3%AE%C2%BAb-inducing-kinase-suppresses-mll-af9-induced-acute-myeloid-leukemia
#6
Yan Xiu, Qianze Dong, Qingchang Li, Fengyin Li, Nick Borcherding, Weizhou Zhang, Brendan Boyce, Hai-Hui Xue, Chen Zhao
Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabilization of NIK-induced activation of NF-κB non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29317678/peptidomimetic-blockade-of-myb-in-acute-myeloid-leukemia
#7
Kavitha Ramaswamy, Lauren Forbes, Gerard Minuesa, Tatyana Gindin, Fiona Brown, Michael G Kharas, Andrei V Krivtsov, Scott A Armstrong, Eric Still, Elisa de Stanchina, Birgit Knoechel, Richard Koche, Alex Kentsis
Aberrant gene expression is a hallmark of acute leukemias. MYB-driven transcriptional coactivation with CREB-binding protein (CBP)/P300 is required for acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex and rapidly accumulates in the nuclei of AML cells. Treatment of AML cells with MYBMIM led to the dissociation of the MYB:CBP/P300 complex in cells, its displacement from oncogenic enhancers enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes...
January 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29309032/correction-replication-study-inhibition-of-bet-recruitment-to-chromatin-as-an-effective-treatment-for-mll-fusion-leukaemia
#8
Xiaochuan Shan, Juan José Fung, Alan Kosaka, Gwenn Danet-Desnoyers
No abstract text is available yet for this article.
January 8, 2018: ELife
https://www.readbyqxmd.com/read/29307605/megakaryocyte-derived-excessive-tgf%C3%AE-1-inhibits-proliferation-of-normal-hematopoietic-stem-cells-in-acute-myeloid-leukemia
#9
Yuemin Gong, Mei Zhao, Wanzhu Yang, Ai Gao, Xiuxiu Yin, Linping Hu, Xiaofang Wang, Jing Xu, Sha Hao, Tao Cheng, Hui Cheng
Impaired production of healthy hematopoietic cells from residual hematopoietic stem cells (HSCs) leads to high mortality in acute myeloid leukemia (AML). Previous studies have identified p21 and Egr3 as intrinsic factors responsible for the growth arrest and differentiation blockade of normal HSCs in leukemia, however, the related extrinsic factors remains unknown. In this study, we demonstrated that TGFβ signaling was up-regulated in HSCs from MLL-AF9 induced AML mice bone marrow, due to excessive production of TGFβ1 especially from megakaryocytes, and over-activation of latent TGFβ1 protein...
January 4, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29306107/leukemia-cells-impair-normal-hematopoiesis-and-induce-functionally-loss-of-hematopoietic-stem-cells-through-immune-cells-and-inflammation
#10
Ping Cui, Yuhua Zhang, Maoxiang Cui, Zhihong Li, Guang Ma, Rufeng Wang, Ning Wang, Shujuan Huang, Jie Gao
Bone marrow (BM) failure is often seen in leukemia patients, indicating an abnormal hematopoietic process. However, hematopoiesis in leukemic milieus is largely unknown. In the present study, we utilized one of the most frequent leukemogenic translocations MLL-AF9 to induce leukemia and investigated the hematopoiesis and the activity of hematopoietic stem and progenitor cells (HSPCs) in a leukemic milieu. We found that the phenotypes of the non-leukemic population in leukemic BM were drastically different than normal BM, including blockage of differentiation and a drastically reduced Lin-/Sca+/c-kit+ (LSK) population that contains all HSPCs in leukemic BM...
January 2, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29296851/agonistic-targeting-of-tlr1-tlr2-induces-p38-mapk-dependent-apoptosis-and-nf%C3%AE%C2%BAb-dependent-differentiation-of-aml-cells
#11
Mia Eriksson, Pablo Peña-Martínez, Ramprasad Ramakrishnan, Marion Chapellier, Carl Högberg, Gabriella Glowacki, Christina Orsmark-Pietras, Talía Velasco-Hernández, Vladimir Lj Lazarević, Gunnar Juliusson, Jörg Cammenga, James C Mulloy, Johan Richter, Thoas Fioretos, Benjamin L Ebert, Marcus Järås
Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+CD38- cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 in MLL-AF9-driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NFκB-dependent manner...
October 24, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296788/mll-af9-leukemias-are-sensitive-to-parp1-inhibitors-combined-with-cytotoxic-drugs
#12
Silvia Maifrede, Esteban Martinez, Margaret Nieborowska-Skorska, Daniela Di Marcantonio, Michael Hulse, Bac Viet Le, Huaqing Zhao, Katarzyna Piwocka, Italo Tempera, Stephen M Sykes, Tomasz Skorski
PARP1 is required for the maintenance of MLL-AF9 leukemias.PARP1 inhibitors enhance the therapeutic effect of cytotoxic drugs against MLL-AF9 leukemias.
August 22, 2017: Blood Advances
https://www.readbyqxmd.com/read/29284071/design-of-the-first-in-class-highly-potent-irreversible-inhibitor-targeting-the-menin-mll-protein-protein-interaction
#13
Shaomeng Wang, Shilin Xu, Angelo Aguilar, Tianfeng Xu, Ke Zheng, Liyue Huang, Jeanne Stuckey, Krishnapriya Chinnaswamy, Denzil Bernard, Ester Fernández-Salas, Liu Liu, Mi Wang, Donna McEachern, Sally Przybranowski, Caroline Foster
: We report the structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is >30-times more potent than its corresponding reversible inhibitors. Mass spectroscopic analysis and co-crystal structure of M-525 in complex with menin firmly establish its mode of action...
December 28, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/29249820/setd2-mediated-crosstalk-between-h3k36me3-and-h3k79me2-in-mll-rearranged-leukemia
#14
J Bu, A Chen, X Yan, F He, Y Dong, Y Zhou, J He, D Zhan, P Lin, Y Hayashi, Y Sun, Y Zhang, Z Xiao, H L Grimes, Q-F Wang, G Huang
Previously, we identified SETD2 loss-of-function mutations in 22% of MLL-rearranged (MLLr) acute leukemia patients, implicating a mechanism for cooperativity between SETD2 mutations and MLL fusions. However, the detailed mechanism of how SETD2-H3K36me3 downregulation accelerates MLLr leukemia remains unclear. Here, we show that in MLLr leukemia, both H3K79me2 and H3K36me3 are aberrantly elevated and co-enriched in a group of genes. SETD2 inactivation leads to a global reduction of H3K36me3 and a further elevation of H3K79me2, but does not change the expression of known MLL fusion target genes...
December 18, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29241110/design-synthesis-and-initial-evaluation-of-affinity-based-small-molecular-probe-for-detection-of-wdr5
#15
Wei-Lin Chen, Dong-Dong Li, Zhi-Hui Wang, Xiao-Li Xu, Xiao-Jin Zhang, Zheng-Yu Jiang, Xiao-Ke Guo, Qi-Dong You
WDR5, a subunit of the SET/MLL complex, plays critical roles in various biological progresses and are abnormally expressed in many cancers. Here we report the design, synthesis, and biochemical characterization of a new chemical tool to capture WDR5 protein. The probe is a biotinylated version of compound 30 that is a potent WDR5 inhibitor we previously reported. Importantly, the probe displayed high affinity to WDR5 protein in vitro binding potency and showed the ability in specifically and real time monitoring WDR5 protein...
November 28, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29240787/brd3-4-inhibition-and-flt3-ligand-deprivation-target-pathways-that-are-essential-for-the-survival-of-human-mll-af9-leukemic-cells
#16
Marco Carretta, Annet Z Brouwers-Vos, Matthieu Bosman, Sarah J Horton, Joost H A Martens, Edo Vellenga, Jan Jacob Schuringa
In the present work we aimed to identify targetable signaling networks in human MLL-AF9 leukemias. We show that MLL-AF9 cells critically depend on FLT3-ligand induced pathways as well as on BRD3/4 for their survival. We evaluated the in vitro and in vivo efficacy of the BRD3/4 inhibitor I-BET151 in various human MLL-AF9 (primary) models and patient samples and analyzed the transcriptome changes following treatment. To further understand the mode of action of BRD3/4 inhibition, we performed ChIP-seq experiments on the MLL-AF9 complex in THP1 cells and compared it to RNA-seq data of I-BET151 treated cells...
2017: PloS One
https://www.readbyqxmd.com/read/29235481/targeted-inhibition-of-stat-tet1-axis-as-a-therapeutic-strategy-for-acute-myeloid-leukemia
#17
Xi Jiang, Chao Hu, Kyle Ferchen, Ji Nie, Xiaolong Cui, Chih-Hong Chen, Liting Cheng, Zhixiang Zuo, William Seibel, Chunjiang He, Yixuan Tang, Jennifer R Skibbe, Mark Wunderlich, William C Reinhold, Lei Dong, Chao Shen, Stephen Arnovitz, Bryan Ulrich, Jiuwei Lu, Hengyou Weng, Rui Su, Huilin Huang, Yungui Wang, Chenying Li, Xi Qin, James Mulloy, Yi Zheng, Jiajie Diao, Jie Jin, Chong Li, Paul P Liu, Chuan He, Yuan Chen, Jianjun Chen
Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML...
December 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29228680/long-noncoding-rna-miat-promotes-non-small-cell-lung-cancer-proliferation-and-metastasis-through-mmp9-activation
#18
I-Lu Lai, Chin-An Yang, Pei-Chin Lin, Wen-Ling Chan, Ya-Ting Lee, Ju-Chen Yen, Ya-Sian Chang, Jan-Gowth Chang
Long noncoding RNAs (lncRNAs) play crucial roles in carcinogenesis. Myocardial infarction-associated transcript (MIAT), originally isolated as a candidate gene for myocardial infarction, has been found to act as an oncogene in chronic lymphocytic leukaemias and neuroendocrine prostate cancer (NEPC); however, little is known about its expression pattern, biological function, and underlying mechanism in non-small cell lung cancer (NSCLC). In this study, we observed that MIAT expression was upregulated in NSCLC, and its overexpression was associated with advanced tumor stage...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29224319/-screening-of-adult-ph-like-acute-lymphoblastic-leukemia-by-multiplex-real-time-quantitative-pcr
#19
M Z Xu, Q Y Fang, X Y Gong, J Feng, Y J Jia, Q H Li, K Q Liu, X L Zhao, K Ru, Z Tian, K J Tang, M Wang, J X Wang, Y C Mi
Objective: To investigate the feasibility of multiplex real-time RT-PCR with fluorescent probes in early screening of Ph-like acute lymphoblastic leukemia (ALL) and analyze the clinical feature and prognos. Method: A total of 118 adult B-ALL patients diagnosed between October 2010 and March 2016 were enrolled in this study. Multiplex RT-PCR was used to detect the Ph-like ALL related fusion gene and CRLF2 expression in 58 BCR-ABL and MLL rearrangement negative patients. The clinical features, treatment response and prognosis were analyzed in Ph-like fusion gene positive and/or CRLF2 over-expression patients...
November 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29217648/the-interaction-of-enl-with-paf1-mitigates-polycomb-silencing-and-facilitates-murine-leukemogenesis
#20
Katrin Hetzner, Maria-Paz Garcia-Cuellar, Christian Büttner, Robert K Slany
ENL is a chromatin reader present in complexes stimulating transcriptional elongation. It is fused to MLL in leukemia and missense mutations have been identified in Wilms' tumor and AML. Here we demonstrate that ENL overcomes polycomb silencing through recruitment of PAF1 via the conserved YEATS domain that recognizes acetylated histone H3. PAF1 was responsible for anti-repressive activities of ENL in vitro and it determined the transforming potential of MLL-ENL. MLL-ENL target loci showed supraphysiological PAF1 binding, hyper-ubiquitination of histone H2B and hypomodification with H2AUb resulting in accelerated transcription rates...
December 7, 2017: Blood
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