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JOURNAL ARTICLE
Angela Maria Savino, Sara Isabel Fernandes, Orianne Olivares, Anna Zemlyansky, Antony Cousins, Elke K Markert, Shani Barel, Ifat Geron, Liron Frishman, Yehudit Birger, Cornelia Eckert, Sergey Tumanov, Gillian MacKay, Jurre J Kamphorst, Pawel Herzyk, Jonatan Fernández-García, Ifat Abramovich, Inbal Mor, Michela Bardini, Ersilia Barin, Sudha Janaki-Raman, Justin R Cross, Michael G Kharas, Eyal Gottlieb, Shai Izraeli, Christina Halsey
Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty-acid synthesis in CNS leukemia, highlighting Stearoyl-CoA desaturase ( SCD1 ) as a key player. In vivo SCD1 overexpression increases CNS disease, whilst genetic or pharmacological inhibition of SCD1 decreases CNS load...
October 2020: Nature Cancer
#22
JOURNAL ARTICLE
Melody Allensworth-James, Jewel Banik, Angela Odle, Linda Hardy, Alex Lagasse, Ana Rita Silva Moreira, Jordan Bird, Christian L Thomas, Nathan Avaritt, Michael G Kharas, Christopher J Lengner, Stephanie D Byrum, Melanie C MacNicol, Gwen V Childs, Angus M MacNicol
The adipokine leptin regulates energy homeostasis through ubiquitously expressed leptin receptors. Leptin has a number of major signaling targets in the brain, including cells of the anterior pituitary (AP). We have previously reported that mice lacking leptin receptors in AP somatotropes display growth hormone (GH) deficiency, metabolic dysfunction, and adult-onset obesity. Among other targets, leptin signaling promotes increased levels of the pituitary transcription factor POU1F1, which in turn regulates the specification of somatotrope, lactotrope, and thyrotrope cell lineages within the AP...
March 1, 2021: Endocrinology
#23
JOURNAL ARTICLE
Sangmoo Jeong, Angela Maria Savino, Rachel Chirayil, Ersilia Barin, Yuanming Cheng, Sun-Mi Park, Alexandra Schurer, Edouard Mullarky, Lewis C Cantley, Michael G Kharas, Kayvan R Keshari
A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions...
January 5, 2021: Cell Metabolism
#24
JOURNAL ARTICLE
Mauro Montalbano, Salome McAllen, Nicha Puangmalai, Urmi Sengupta, Nemil Bhatt, Omar D Johnson, Michael G Kharas, Rakez Kayed
Oligomeric assemblies of tau and the RNA-binding proteins (RBPs) Musashi (MSI) are reported in Alzheimer's disease (AD). However, the role of MSI and tau interaction in their aggregation process and its effects are nor clearly known in neurodegenerative diseases. Here, we investigated the expression and cellular localization of MSI1 and MSI2 in the brains tissues of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as in the wild-type mice and tau knock-out and P301L tau mouse models...
August 27, 2020: Nature Communications
#25
JOURNAL ARTICLE
Sang-Gyu Lee, Teja Muralidhar Kalidindi, Hanzhi Lou, Kishore Gangangari, Blesida Punzalan, Ariana Bitton, Casey J Lee, Hebert A Vargas, Soobin Park, Lisa Bodei, Michael G Kharas, Vijay K Singh, Naga Vara Kishore Pillarsetty, Steven M Larson
With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of γ-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy. Methods: GT3 was loaded into liposomes using passive loading. 64 Cu-GT3-Nano and 3 H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually...
April 2021: Journal of Nuclear Medicine
#26
COMMENT
Yuanming Cheng, Hanzhi Luo, Michael G Kharas
In this issue of Cell Stem Cell, Shen et al. (2020) and Wang et al. (2020) independently identify the essential function of m6 A demethylase ALKBH5 in maintaining myeloid leukemia stem cells. These studies expand the regulators of the epitranscriptome that are required for acute myeloid leukemia (AML) development.
July 2, 2020: Cell Stem Cell
#27
JOURNAL ARTICLE
Josephine Wesely, Andriana G Kotini, Franco Izzo, Hanzhi Luo, Han Yuan, Jun Sun, Maria Georgomanoli, Asaf Zviran, André G Deslauriers, Neville Dusaj, Stephen D Nimer, Christina Leslie, Dan A Landau, Michael G Kharas, Eirini P Papapetrou
Leukemia stem cells (LSCs) are believed to have more distinct vulnerabilities than the bulk acute myeloid leukemia (AML) cells, but their rarity and the lack of universal markers for their prospective isolation hamper their study. We report that genetically clonal induced pluripotent stem cells (iPSCs) derived from an AML patient and characterized by exceptionally high engraftment potential give rise, upon hematopoietic differentiation, to a phenotypic hierarchy. Through fate-tracking experiments, xenotransplantation, and single-cell transcriptomics, we identify a cell fraction (iLSC) that can be isolated prospectively by means of adherent in vitro growth that resides on the apex of this hierarchy and fulfills the hallmark features of LSCs...
June 2, 2020: Cell Reports
#28
JOURNAL ARTICLE
Kulandaimanuvel Antony Michealraj, Sachin A Kumar, Leo J Y Kim, Florence M G Cavalli, David Przelicki, John B Wojcik, Alberto Delaidelli, Andrea Bajic, Olivier Saulnier, Graham MacLeod, Ravi N Vellanki, Maria C Vladoiu, Paul Guilhamon, Winnie Ong, John J Y Lee, Yanqing Jiang, Borja L Holgado, Alex Rasnitsyn, Ahmad A Malik, Ricky Tsai, Cory M Richman, Kyle Juraschka, Joonas Haapasalo, Evan Y Wang, Pasqualino De Antonellis, Hiromichi Suzuki, Hamza Farooq, Polina Balin, Kaitlin Kharas, Randy Van Ommeren, Olga Sirbu, Avesta Rastan, Stacey L Krumholtz, Michelle Ly, Moloud Ahmadi, Geneviève Deblois, Dilakshan Srikanthan, Betty Luu, James Loukides, Xiaochong Wu, Livia Garzia, Vijay Ramaswamy, Evgeny Kanshin, María Sánchez-Osuna, Ibrahim El-Hamamy, Fiona J Coutinho, Panagiotis Prinos, Sheila Singh, Laura K Donovan, Craig Daniels, Daniel Schramek, Mike Tyers, Samuel Weiss, Lincoln D Stein, Mathieu Lupien, Bradly G Wouters, Benjamin A Garcia, Cheryl H Arrowsmith, Poul H Sorensen, Stephane Angers, Nada Jabado, Peter B Dirks, Stephen C Mack, Sameer Agnihotri, Jeremy N Rich, Michael D Taylor
Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen...
June 11, 2020: Cell
#29
JOURNAL ARTICLE
Laura K Donovan, Alberto Delaidelli, Sujith K Joseph, Kevin Bielamowicz, Kristen Fousek, Borja L Holgado, Alex Manno, Dilakshan Srikanthan, Ahmed Z Gad, Randy Van Ommeren, David Przelicki, Cory Richman, Vijay Ramaswamy, Craig Daniels, Jonelle G Pallota, Tajana Douglas, Alyssa C M Joynt, Joonas Haapasalo, Carolina Nor, Maria C Vladoiu, Claudia M Kuzan-Fischer, Livia Garzia, Stephen C Mack, Srinidhi Varadharajan, Matthew L Baker, Liam Hendrikse, Michelle Ly, Kaitlin Kharas, Polina Balin, Xiaochong Wu, Lei Qin, Ning Huang, Ana Guerreiro Stucklin, A Sorana Morrissy, Florence M G Cavalli, Betty Luu, Raul Suarez, Pasqualino De Antonellis, Antony Michealraj, Avesta Rastan, Meenakshi Hegde, Martin Komosa, Olga Sirbu, Sachin A Kumar, Zied Abdullaev, Claudia C Faria, Stephen Yip, Juliette Hukin, Uri Tabori, Cynthia Hawkins, Ken Aldape, Mads Daugaard, John M Maris, Poul H Sorensen, Nabil Ahmed, Michael D Taylor
Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain...
May 2020: Nature Medicine
#30
JOURNAL ARTICLE
Diu T T Nguyen, Yuheng Lu, Karen L Chu, Xuejing Yang, Sun-Mi Park, Zi-Ning Choo, Christopher R Chin, Camila Prieto, Alexandra Schurer, Ersilia Barin, Angela M Savino, Saroj Gourkanti, Payal Patel, Ly P Vu, Christina S Leslie, Michael G Kharas
The cell-context dependency for RNA binding proteins (RBPs) mediated control of stem cell fate remains to be defined. Here we adapt the HyperTRIBE method using an RBP fused to a Drosophila RNA editing enzyme (ADAR) to globally map the mRNA targets of the RBP MSI2 in mammalian adult normal and malignant stem cells. We reveal a unique MUSASHI-2 (MSI2) mRNA binding network in hematopoietic stem cells that changes during transition to multipotent progenitors. Additionally, we discover a significant increase in RNA binding activity of MSI2 in leukemic stem cells compared with normal hematopoietic stem and progenitor cells, resulting in selective regulation of MSI2's oncogenic targets...
April 24, 2020: Nature Communications
#31
JOURNAL ARTICLE
Yuan Qi, Youhan Fang, David R Sinclair, Shangqin Guo, Meritxell Alberich-Jorda, Jun Lu, Daniel G Tenen, Michael G Kharas, Saumyadipta Pyne
A new computational framework for FLow cytometric Analysis of Rare Events (FLARE) has been developed specifically for fast and automatic identification of rare cell populations in very large samples generated by platforms like multi-parametric flow cytometry. Using a hierarchical Bayesian model and information-sharing via parallel computation, FLARE rapidly explores the high-dimensional marker-space to detect highly rare populations that are consistent across multiple samples. Further it can focus within specified regions of interest in marker-space to detect subpopulations with desired precision...
2020: PloS One
#32
JOURNAL ARTICLE
Saskia Hendriks, Christine Grady, Khara M Ramos, Winston Chiong, Joseph J Fins, Paul Ford, Sara Goering, Henry T Greely, Katrina Hutchison, Michael L Kelly, Scott Y H Kim, Eran Klein, Sarah H Lisanby, Helen Mayberg, Hannah Maslen, Franklin G Miller, Karen Rommelfanger, Sameer A Sheth, Anna Wexler
Importance: Developing more and better diagnostic and therapeutic tools for central nervous system disorders is an ethical imperative. Human research with neural devices is important to this effort and a critical focus of the National Institutes of Health Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Despite regulations and standard practices for conducting ethical research, researchers and others seek more guidance on how to ethically conduct neural device studies...
October 17, 2019: JAMA Neurology
#33
JOURNAL ARTICLE
Camila Prieto, Michael G Kharas
Posttranscriptional regulation of mRNA is a powerful and tightly controlled process in which cells command the integrity, diversity, and abundance of their protein products. RNA-binding proteins (RBPs) are the principal players that control many intermediary steps of posttranscriptional regulation. Recent advances in this field have discovered the importance of RBPs in hematological diseases. Herein we will review a number of RBPs that have been determined to play critical functions in leukemia and lymphoma...
October 15, 2019: Cold Spring Harbor Perspectives in Medicine
#34
JOURNAL ARTICLE
Yuanming Cheng, Hanzhi Luo, Franco Izzo, Brian F Pickering, Diu Nguyen, Robert Myers, Alexandra Schurer, Saroj Gourkanti, Jens C Brüning, Ly P Vu, Samie R Jaffrey, Dan A Landau, Michael G Kharas
Stem cells balance cellular fates through asymmetric and symmetric divisions in order to self-renew or to generate downstream progenitors. Symmetric commitment divisions in stem cells are required for rapid regeneration during tissue damage and stress. The control of symmetric commitment remains poorly defined. Using single-cell RNA sequencing (scRNA-seq) in combination with transcriptomic profiling of HSPCs (hematopoietic stem and progenitor cells) from control and m6 A methyltransferase Mettl3 conditional knockout mice, we found that m6 A-deficient hematopoietic stem cells (HSCs) fail to symmetrically differentiate...
August 13, 2019: Cell Reports
#35
JOURNAL ARTICLE
Justin Taylor, Maria Sendino, Alexander N Gorelick, Alessandro Pastore, Matthew T Chang, Alexander V Penson, Elena I Gavrila, Connor Stewart, Ella M Melnik, Florisela Herrejon Chavez, Lillian Bitner, Akihide Yoshimi, Stanley Chun-Wei Lee, Daichi Inoue, Bo Liu, Xiao J Zhang, Anthony R Mato, Ahmet Dogan, Michael G Kharas, Yuhong Chen, Demin Wang, Rajesh K Soni, Ronald C Hendrickson, Gorka Prieto, Jose A Rodriguez, Barry S Taylor, Omar Abdel-Wahab
Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer and XPO1 has been a focus of anti-cancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1. XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy in vivo...
July 8, 2019: Cancer Discovery
#36
JOURNAL ARTICLE
Gerard Minuesa, Steven K Albanese, Wei Xie, Yaniv Kazansky, Daniel Worroll, Arthur Chow, Alexandra Schurer, Sun-Mi Park, Christina Z Rotsides, James Taggart, Andrea Rizzi, Levi N Naden, Timothy Chou, Saroj Gourkanti, Daniel Cappel, Maria C Passarelli, Lauren Fairchild, Carolina Adura, J Fraser Glickman, Jessica Schulman, Christopher Famulare, Minal Patel, Joseph K Eibl, Gregory M Ross, Shibani Bhattacharya, Derek S Tan, Christina S Leslie, Thijs Beuming, Dinshaw J Patel, Yehuda Goldgur, John D Chodera, Michael G Kharas
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model...
June 19, 2019: Nature Communications
#37
REVIEW
Ly P Vu, Yuanming Cheng, Michael G Kharas
Hematopoietic development and differentiation are highly regulated processes, and recent studies focusing on m6 A mRNA methylation have uncovered how this mark controls cell fate in both normal and malignant hematopoietic states. In this review, we focus on how writers, readers, and erasers of RNA methylation can mediate distinct phenotypes on mRNAs and on cells. Targeting the RNA methylation program has emerged as a potential novel therapeutic strategy, and we explore the role for these regulators in both normal and dysregulated cell contexts...
January 2019: Cancer Discovery
#38
JOURNAL ARTICLE
Sun-Mi Park, Hyunwoo Cho, Angela M Thornton, Trevor S Barlowe, Timothy Chou, Sagar Chhangawala, Lauren Fairchild, James Taggart, Arthur Chow, Alexandria Schurer, Antoine Gruet, Matthew D Witkin, Jun Hyun Kim, Ethan M Shevach, Andrei Krivtsov, Scott A Armstrong, Christina Leslie, Michael G Kharas
Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia. IKZF2 is highly expressed in leukemic stem cells (LSCs), and its deficiency results in defective LSC function. IKZF2 depletion in acute myeloid leukemia (AML) cells reduced colony formation, increased differentiation and apoptosis, and delayed leukemogenesis...
January 3, 2019: Cell Stem Cell
#39
JOURNAL ARTICLE
David Jee, Jr-Shiuan Yang, Sun-Mi Park, D'Juan T Farmer, Jiayu Wen, Timothy Chou, Arthur Chow, Michael T McManus, Michael G Kharas, Eric C Lai
While Slicer activity of Argonaute is central to RNAi, conserved roles of slicing in endogenous regulatory biology are less clear, especially in mammals. Biogenesis of erythroid Dicer-independent mir-451 involves Ago2 catalysis, but mir-451-KO mice do not phenocopy Ago2 catalytic-dead (Ago2-CD) mice, suggesting other needs for slicing. Here, we reveal mir-486 as another dominant erythroid miRNA with atypical biogenesis. While it is Dicer dependent, it requires slicing to eliminate its star strand. Thus, in Ago2-CD conditions, miR-486-5p is functionally inactive due to duplex arrest...
January 18, 2018: Molecular Cell
#40
JOURNAL ARTICLE
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
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