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https://www.readbyqxmd.com/read/29320732/stabilization-of-nf-%C3%AE%C2%BAb-inducing-kinase-suppresses-mll-af9-induced-acute-myeloid-leukemia
#1
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/29306107/leukemia-cells-impair-normal-hematopoiesis-and-induce-functionally-loss-of-hematopoietic-stem-cells-through-immune-cells-and-inflammation
#2
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
#3
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
#4
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/29240787/brd3-4-inhibition-and-flt3-ligand-deprivation-target-pathways-that-are-essential-for-the-survival-of-human-mll-af9-leukemic-cells
#5
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/29154208/characteristics-of-nk-cells-from-leukemic-microenvironment-in-mll-af9-induced-acute-myeloid-leukemia
#6
Feifei Yang, Rong Wang, Wenli Feng, Chong Chen, Xiao Yang, Lina Wang, Yuting Hu, Qian Ren, Guoguang Zheng
NK cells are indispensable components of tissue microenvironment and play vital in both innate and adaptive immunity. The activation and function of NK cells are affected by tumor microenvironments. NK cells are also important players in leukemic microenvironment. However, their characteristics in leukemic microenvironment, including maturation status, phenotype, subpopulations and functional roles especially immunoregulatory potential, have not been well established. Here, we studied these characteristics of NK cells in MLL-AF9 induced mouse acute myeloid leukemia (AML) model...
November 16, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/29152105/necdin-modulates-leukemia-initiating-cell-quiescence-and-chemotherapy-response
#7
Chonghua Yao, Michihiro Kobayashi, Sisi Chen, Sarah C Nabinger, Rui Gao, Stephen Z Liu, Takashi Asai, Yan Liu
Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29127121/pkc-epsilon-is-a-key-regulator-of-mitochondrial-redox-homeostasis-in-acute-myeloid-leukemia
#8
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/29067751/monitoring-of-fusion-gene-transcripts-to-predict-relapses-in-pediatric-acute-myeloid-leukemia
#9
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/29043883/structural-maintenance-of-chromosomes-4-is-required-for-leukemia-stem-cell-maintenance-in-mll-af9-induced-acute-myeloid-leukemia
#10
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/29018079/setd2-alterations-impair-dna-damage-recognition-and-lead-to-resistance-to-chemotherapy-in-leukemia
#11
Brenton G Mar, S Haihua Chu, Josephine D Kahn, Andrei V Krivtsov, Richard Koche, Cecilia A Castellano, Jacob L Kotlier, Rebecca L Zon, Marie E McConkey, Jonathan Chabon, Ryan Chappell, Peter V Grauman, James J Hsieh, Scott A Armstrong, Benjamin L Ebert
Mutations in SETD2, encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia. We investigated the impact of SETD2 mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of Setd2. SETD2 mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non-DNA damaging agent, l-asparaginase. H3K36me3 localizes components of the DNA damage response (DDR) pathway and SETD2 mutation impaired DDR, blunting apoptosis induced by cytotoxic chemotherapy...
December 14, 2017: Blood
https://www.readbyqxmd.com/read/28974232/the-stem-cell-factor-sall4-is-an-essential-transcriptional-regulator-in-mixed-lineage-leukemia-rearranged-leukemogenesis
#12
Lina Yang, Li Liu, Hong Gao, Jaya Pratap Pinnamaneni, Deepthi Sanagasetti, Vivek P Singh, Kai Wang, Megumi Mathison, Qianzi Zhang, Fengju Chen, Qianxing Mo, Todd Rosengart, Jianchang Yang
BACKGROUND: The stem cell factor spalt-like transcription factor 4 (SALL4) plays important roles in normal hematopoiesis and also in leukemogenesis. We previously reported that SALL4 exerts its effect by recruiting important epigenetic factors such as DNA methyltransferases DNMT1 and lysine-specific demethylase 1 (LSD1/KDM1A). Both of these proteins are critically involved in mixed lineage leukemia (MLL)-rearranged (MLL-r) leukemia, which has a very poor clinical prognosis. Recently, SALL4 has been further linked to the functions of MLL and its target gene homeobox A9 (HOXA9)...
October 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28892146/murine-retrovirally-transduced-bone-marrow-engraftment-models-of-mll-fusion-driven-acute-myelogenous-leukemias-aml
#13
Matthew C Stubbs, Andrei V Krivtsov
MLL-rearranged leukemia represents approximately 5% to 10% of adult acute myelogenous leukemia (AML) and nearly half of all infant/pediatric acute leukemia cases. These leukemias have a poor prognosis, and there are no approved therapeutic options. The rearrangement in the MLL gene leads to aberrant expression of MLL-fusion proteins. These are transforming in murine bone marrow and, in particular, on stem cells and myeloid progenitors derived from bone marrow or fetal liver. The commonality of the MLL fusions is the in-frame fusion of 8 to 11 N-terminal exons of MLL1 (KMT2a) with the C-terminus of a partner fusion gene...
September 11, 2017: Current Protocols in Pharmacology
https://www.readbyqxmd.com/read/28886273/parpi-potentiates-with-current-conventional-therapy-in-mll-leukemia
#14
Lu Zhao, Chi Wai Eric So
Acute myeloid leukemias driven by MLL fusion proteins are commonly associated with poor prognosis and refractory treatment. Here, we provide evidence that olaparib can potentiate sensitivity of MLL leukemia cells to conventional chemotherapy and DNMT inhibitors offering new potential therapeutic strategies for MLL rearranged leukemias Using the primary mouse leukemia cells and human MLL-AF9 leukemic cell line, we demonstrate that treatment of MLL-AF9 leukemic cells with DNMT inhibitors or chemotherapies in combination with olaparib results in significant reduction in colony formation or cell growth while the single agent treatments had little impacts...
October 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28741798/novel-orally-bioavailable-ezh1-2-dual-inhibitors-with-greater-antitumor-efficacy-than-an-ezh2-selective-inhibitor
#15
COMPARATIVE STUDY
Daisuke Honma, Osamu Kanno, Jun Watanabe, Junzo Kinoshita, Makoto Hirasawa, Emi Nosaka, Machiko Shiroishi, Takeshi Takizawa, Isao Yasumatsu, Takao Horiuchi, Akira Nakao, Keisuke Suzuki, Tomonori Yamasaki, Katsuyoshi Nakajima, Miho Hayakawa, Takanori Yamazaki, Ajay Singh Yadav, Nobuaki Adachi
Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis...
October 2017: Cancer Science
https://www.readbyqxmd.com/read/28733386/mir-99-regulates-normal-and-malignant-hematopoietic-stem-cell-self-renewal
#16
Mona Khalaj, Carolien M Woolthuis, Wenhuo Hu, Benjamin H Durham, S Haihua Chu, Sarah Qamar, Scott A Armstrong, Christopher Y Park
The microRNA-99 (miR-99) family comprises a group of broadly conserved microRNAs that are highly expressed in hematopoietic stem cells (HSCs) and acute myeloid leukemia stem cells (LSCs) compared with their differentiated progeny. Herein, we show that miR-99 regulates self-renewal in both HSCs and LSCs. miR-99 maintains HSC long-term reconstitution activity by inhibiting differentiation and cell cycle entry. Moreover, miR-99 inhibition induced LSC differentiation and depletion in an MLL-AF9-driven mouse model of AML, leading to reduction in leukemia-initiating activity and improved survival in secondary transplants...
July 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28650479/aml1-eto-requires-enhanced-c-d-box-snorna-rnp-formation-to-induce-self-renewal-and-leukaemia
#17
Fengbiao Zhou, Yi Liu, Christian Rohde, Cornelius Pauli, Dennis Gerloff, Marcel Köhn, Danny Misiak, Nicole Bäumer, Chunhong Cui, Stefanie Göllner, Thomas Oellerich, Hubert Serve, Maria-Paz Garcia-Cuellar, Robert Slany, Jaroslaw P Maciejewski, Bartlomiej Przychodzen, Barbara Seliger, Hans-Ulrich Klein, Christoph Bartenhagen, Wolfgang E Berdel, Martin Dugas, Makoto Mark Taketo, Daneyal Farouq, Schraga Schwartz, Aviv Regev, Josée Hébert, Guy Sauvageau, Caroline Pabst, Stefan Hüttelmaier, Carsten Müller-Tidow
Leukaemogenesis requires enhanced self-renewal, which is induced by oncogenes. The underlying molecular mechanisms remain incompletely understood. Here, we identified C/D box snoRNAs and rRNA 2'-O-methylation as critical determinants of leukaemic stem cell activity. Leukaemogenesis by AML1-ETO required expression of the groucho-related amino-terminal enhancer of split (AES). AES functioned by inducing snoRNA/RNP formation via interaction with the RNA helicase DDX21. Similarly, global loss of C/D box snoRNAs with concomitant loss of rRNA 2'-O-methylation resulted in decreased leukaemia self-renewal potential...
July 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28646646/antileukemic-activity-and-cellular-effects-of-the-antimalarial-agent-artesunate-in-acute-myeloid-leukemia
#18
Bijender Kumar, Arjun Kalvala, Su Chu, Steven Rosen, Stephen J Forman, Guido Marcucci, Ching-Cheng Chen, Vinod Pullarkat
The artimisinins are a class of antimalarial compounds whose antiparasitic activity is mediated by induction of reactive oxygen species (ROS). Herein, we report that among the artimisinins, artesunate (ARTS), an orally bioavailable compound has the most potent antileukemic activity in AML models and primary patients' blasts. ARTS was most cytotoxic to the FLT3-ITD+ AML MV4-11 and MOLM-13 cells (IC50 values of 1.1 and 0.82μM respectively), inhibited colony formation in primary AML and MDS cells and augmented cytotoxicity of chemotherapeutics...
August 2017: Leukemia Research
https://www.readbyqxmd.com/read/28646565/complete-molecular-remission-in-relapsed-and-refractory-acute-myeloid-leukaemia-with-mll-af9-treated-with-chidamide-based-chemotherapy
#19
Y Lun, J-J Yang, Y Wu
WHAT IS KNOWN AND OBJECTIVE: The mixed lineage leukaemia (MLL) gene translocations are found in approximately 10% of adults with acute myeloid leukaemia (AML) and are markers of poor prognosis. As the best reported response in relapsed and refractory MLL-rearranged AML is around 40%, reinduction treatment is very challenging for those patients. CASE DESCRIPTION: We report a case of relapsed and refractory AML with MLL-AF9, who did not respond to FLAG (fludarabine, cytarabine, granulocyte colony stimulating factor) regimen reinduction treatment, but achieved complete response and molecular remission after chidamide-based chemotherapy...
June 23, 2017: Journal of Clinical Pharmacy and Therapeutics
https://www.readbyqxmd.com/read/28637661/the-full-transforming-capacity-of-mll-af4-is-interlinked-with-lymphoid-lineage-commitment
#20
Shan Lin, Roger T Luo, Mahesh Shrestha, Michael J Thirman, James C Mulloy
Chromosome rearrangements involving the mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The lineage decision of MLL-fusion leukemia is influenced by the fusion partner and microenvironment. To investigate the interplay of fusion proteins and microenvironment in lineage choice, we transplanted human hematopoietic stem and progenitor cells (HSPCs) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly promote myeloid development...
August 17, 2017: Blood
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