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Ravindra Majeti

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https://www.readbyqxmd.com/read/27846387/sticking-it-to-the-niche-cd98-mediates-critical-adhesive-signals-in-aml
#1
Andreas Reinisch, Ravindra Majeti
In this issue of Cancer Cell, Bajaj and colleagues report that CD98, a heterodimeric protein highly expressed in acute myeloid leukemia (AML) and largely dispensable for basal hematopoiesis, plays an important role in facilitating leukemia stem cell adhesion to bone marrow vasculature and is a potential therapeutic target in AML.
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27820943/crispr-cas9-%C3%AE-globin-gene-targeting-in-human-haematopoietic-stem-cells
#2
Daniel P Dever, Rasmus O Bak, Andreas Reinisch, Joab Camarena, Gabriel Washington, Carmencita E Nicolas, Mara Pavel-Dinu, Nivi Saxena, Alec B Wilkens, Sruthi Mantri, Nobuko Uchida, Ayal Hendel, Anupama Narla, Ravindra Majeti, Kenneth I Weinberg, Matthew H Porteus
The β-haemoglobinopathies, such as sickle cell disease and β-thalassaemia, are caused by mutations in the β-globin (HBB) gene and affect millions of people worldwide. Ex vivo gene correction in patient-derived haematopoietic stem cells followed by autologous transplantation could be used to cure β-haemoglobinopathies. Here we present a CRISPR/Cas9 gene-editing system that combines Cas9 ribonucleoproteins and adeno-associated viral vector delivery of a homologous donor to achieve homologous recombination at the HBB gene in haematopoietic stem cells...
November 7, 2016: Nature
https://www.readbyqxmd.com/read/27796738/the-role-of-mutations-in-the-cohesin-complex-in-acute-myeloid-leukemia
#3
REVIEW
Claire Mazumdar, Ravindra Majeti
Mutations in the members of the cohesin complex have recently been identified as early events in acute myeloid leukemia (AML) pathogenesis. Studies conducted by our lab and others have shown that cohesin mutations or knockdown of cohesin subunits impair hematopoietic differentiation and enforce stem cell programs in both human and mouse hematopoiesis. Furthermore, studies in both models demonstrated global changes in chromatin accessibility and structure, in particular increased accessibility at binding sites for hematopoietic stem and progenitor cell (HSPC) transcription factors...
October 28, 2016: International Journal of Hematology
https://www.readbyqxmd.com/read/27732946/autophagy-mediates-proteolysis-of-npm1-and-hexim1-and-sensitivity-to-bet-inhibition-in-aml-cells
#4
Min Huang, Jacqueline S Garcia, Daniel Thomas, Li Zhu, Le Xuan Truong Nguyen, Steven M Chan, Ravindra Majeti, Bruno C Medeiros, Beverly S Mitchell
The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1...
October 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27526324/lineage-specific-and-single-cell-chromatin-accessibility-charts-human-hematopoiesis-and-leukemia-evolution
#5
M Ryan Corces, Jason D Buenrostro, Beijing Wu, Peyton G Greenside, Steven M Chan, Julie L Koenig, Michael P Snyder, Jonathan K Pritchard, Anshul Kundaje, William J Greenleaf, Ravindra Majeti, Howard Y Chang
We define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types that span the hematopoietic hierarchy. Exploiting the finding that the enhancer landscape better reflects cell identity than mRNA levels, we enable 'enhancer cytometry' for enumeration of pure cell types from complex populations. We identify regulators governing hematopoietic differentiation and further show the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia (AML), chromatin accessibility uncovers unique regulatory evolution in cancer cells with a progressively increasing mutation burden...
October 2016: Nature Genetics
https://www.readbyqxmd.com/read/27428079/alkylator-induced-and-patient-derived-xenograft-mouse-models-of-therapy-related-myeloid-neoplasms-model-clinical-disease-and-suggest-the-presence-of-multiple-cell-subpopulations-with-leukemia-stem-cell-activity
#6
Brian A Jonas, Carl Johnson, Dita Gratzinger, Ravindra Majeti
Acute myeloid leukemia (AML) is a heterogeneous group of aggressive bone marrow cancers arising from transformed hematopoietic stem and progenitor cells (HSPC). Therapy-related AML and MDS (t-AML/MDS) comprise a subset of AML cases occurring after exposure to alkylating chemotherapy and/or radiation and are associated with a very poor prognosis. Less is known about the pathogenesis and disease-initiating/leukemia stem cell (LSC) subpopulations of t-AML/MDS compared to their de novo counterparts. Here, we report the development of mouse models of t-AML/MDS...
2016: PloS One
https://www.readbyqxmd.com/read/27392217/burning-fat-fuels-leukemic-stem-cell-heterogeneity
#7
Daniel Thomas, Ravindra Majeti
Obese leukemia patients exhibit reduced survival after chemotherapy, suggesting an important role of adipose tissue in disease progression. In this issue of Cell Stem Cell, Ye et al. (2016) reveal metabolic heterogeneity in leukemic stem cell (LSC) subpopulations and show that chemotherapy-resistant CD36+ LSCs co-opt gonadal adipose tissue to support their metabolism and survival.
July 7, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27294525/cd47-blocking-immunotherapies-stimulate-macrophage-mediated-destruction-of-small-cell-lung-cancer
#8
Kipp Weiskopf, Nadine S Jahchan, Peter J Schnorr, Sandra Cristea, Aaron M Ring, Roy L Maute, Anne K Volkmer, Jens-Peter Volkmer, Jie Liu, Jing Shan Lim, Dian Yang, Garrett Seitz, Thuyen Nguyen, Di Wu, Kevin Jude, Heather Guerston, Amira Barkal, Francesca Trapani, Julie George, John T Poirier, Eric E Gardner, Linde A Miles, Elisa de Stanchina, Shane M Lofgren, Hannes Vogel, Monte M Winslow, Caroline Dive, Roman K Thomas, Charles M Rudin, Matt van de Rijn, Ravindra Majeti, K Christopher Garcia, Irving L Weissman, Julien Sage
Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment. Disruption of the interaction of CD47 with SIRPα using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture...
July 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27213817/a-humanized-bone-marrow-ossicle-xenotransplantation-model-enables-improved-engraftment-of-healthy-and-leukemic-human-hematopoietic-cells
#9
Andreas Reinisch, Daniel Thomas, M Ryan Corces, Xiaohua Zhang, Dita Gratzinger, Wan-Jen Hong, Katharina Schallmoser, Dirk Strunk, Ravindra Majeti
Xenotransplantation models represent powerful tools for the investigation of healthy and malignant human hematopoiesis. However, current models do not fully mimic the components of the human bone marrow (BM) microenvironment, and they enable only limited engraftment of samples from some human malignancies. Here we show that a xenotransplantation model bearing subcutaneous humanized ossicles with an accessible BM microenvironment, formed by in situ differentiation of human BM-derived mesenchymal stromal cells, enables the robust engraftment of healthy human hematopoietic stem and progenitor cells, as well as primary acute myeloid leukemia (AML) samples, at levels much greater than those in unmanipulated mice...
July 2016: Nature Medicine
https://www.readbyqxmd.com/read/27154821/ash1l-links-histone-h3-lysine-36-dimethylation-to-mll-leukemia
#10
Li Zhu, Qin Li, Stephen H K Wong, Min Huang, Brianna J Klein, Jinfeng Shen, Larissa Ikenouye, Masayuki Onishi, Dominik Schneidawind, Corina Buechele, Loren Hansen, Jesús Duque-Afonso, Fangfang Zhu, Gloria Mas Martin, Or Gozani, Ravindra Majeti, Tatiana G Kutateladze, Michael L Cleary
UNLABELLED: Numerous studies in multiple systems support that histone H3 lysine 36 dimethylation (H3K36me2) is associated with transcriptional activation; however, the underlying mechanisms are not well defined. Here, we show that the H3K36me2 chromatin mark written by the ASH1L histone methyltransferase is preferentially bound in vivo by LEDGF, a mixed-lineage leukemia (MLL)-associated protein that colocalizes with MLL, ASH1L, and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild-type MLL proteins to chromatin at key leukemia target genes and is a crucial regulator of MLL-dependent transcription and leukemic transformation...
July 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27126995/sirp%C3%AE-antibody-fusion-proteins-selectively-bind-and-eliminate-dual-antigen-expressing-tumor-cells
#11
Emily C Piccione, Silvia Juarez, Serena Tseng, Jie Liu, Melissa Stafford, Cyndhavi Narayanan, Lijuan Wang, Kipp Weiskopf, Ravindra Majeti
PURPOSE: CD47 is highly expressed on a variety of tumor cells. The interaction of CD47 with SIRPα, a protein on phagocytic cells, transmits a "don't eat me" signal that negatively regulates phagocytosis. CD47-SIRPα antagonists enable phagocytosis by disrupting the inhibitory signal and can synergize with Fc-mediated pro-phagocytic signals for potent elimination of tumor cells. A potential limitation of therapeutic CD47-SIRPα antagonists is that expression of CD47 on normal cells may create sites of toxicity or an "antigen sink...
April 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26607380/leukemia-associated-cohesin-mutants-dominantly-enforce-stem-cell-programs-and-impair-human-hematopoietic-progenitor-differentiation
#12
Claire Mazumdar, Ying Shen, Seethu Xavy, Feifei Zhao, Andreas Reinisch, Rui Li, M Ryan Corces, Ryan A Flynn, Jason D Buenrostro, Steven M Chan, Daniel Thomas, Julie L Koenig, Wan-Jen Hong, Howard Y Chang, Ravindra Majeti
Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs...
December 3, 2015: Cell Stem Cell
https://www.readbyqxmd.com/read/26455528/clonal-evolution-of-preleukemic-hematopoietic-stem-cells-in-acute-myeloid-leukemia
#13
REVIEW
Stephen M Sykes, Konstantinos D Kokkaliaris, Michael D Milsom, Ross L Levine, Ravindra Majeti
Acute myeloid leukemia (AML) is an aggressive blood cancer that results from an abnormal expansion of uncontrollably proliferating myeloid progenitors that have lost the capacity to differentiate. AML encompasses many genetically distinct subtypes that predominantly develop de novo. However, AML can also arise from premalignant myeloid conditions, such as myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs), or develop as the result of exposure to genotoxic agents used to treat unrelated malignancies...
December 2015: Experimental Hematology
https://www.readbyqxmd.com/read/26444494/an-lsc-epigenetic-signature-is-largely-mutation-independent-and-implicates-the-hoxa-cluster-in-aml-pathogenesis
#14
Namyoung Jung, Bo Dai, Andrew J Gentles, Ravindra Majeti, Andrew P Feinberg
Acute myeloid leukaemia (AML) is characterized by subpopulations of leukaemia stem cells (LSCs) that are defined by their ability to engraft in immunodeficient mice. Here we show an LSC DNA methylation signature, derived from xenografts and integration with gene expression that is comprised of 71 genes and identifies a key role for the HOXA cluster. Most of the genes are epigenetically regulated independently of underlying mutations, although several are downstream targets of epigenetic modifier genes mutated in AML...
October 7, 2015: Nature Communications
https://www.readbyqxmd.com/read/26390038/pre-clinical-development-of-a-humanized-anti-cd47-antibody-with-anti-cancer-therapeutic-potential
#15
Jie Liu, Lijuan Wang, Feifei Zhao, Serena Tseng, Cyndhavi Narayanan, Lei Shura, Stephen Willingham, Maureen Howard, Susan Prohaska, Jens Volkmer, Mark Chao, Irving L Weissman, Ravindra Majeti
CD47 is a widely expressed cell surface protein that functions as a regulator of phagocytosis mediated by cells of the innate immune system, such as macrophages and dendritic cells. CD47 serves as the ligand for a receptor on these innate immune cells, SIRP-alpha, which in turn delivers an inhibitory signal for phagocytosis. We previously found increased expression of CD47 on primary human acute myeloid leukemia (AML) stem cells, and demonstrated that blocking monoclonal antibodies directed against CD47 enabled the phagocytosis and elimination of AML, non-Hodgkin's lymphoma (NHL), and many solid tumors in xenograft models...
2015: PloS One
https://www.readbyqxmd.com/read/26111462/biology-and-clinical-relevance-of-acute-myeloid-leukemia-stem-cells
#16
REVIEW
Andreas Reinisch, Steven M Chan, Daniel Thomas, Ravindra Majeti
Evidence for the cancer stem cell model was first demonstrated in xenotransplanted blood and bone marrow samples from patients with acute myeloid leukemia (AML) almost two decades ago, supporting the concept that a rare clonal and mutated leukemic stem cell (LSC) population is sufficient to drive leukemic growth. The inability to eliminate LSCs with conventional therapies is thought to be the primary cause of disease relapse in AML patients, and as such, novel therapies with the ability to target this population are required to improve patient outcomes...
July 2015: Seminars in Hematology
https://www.readbyqxmd.com/read/26083076/a-bispecific-antibody-targeting-cd47-and-cd20-selectively-binds-and-eliminates-dual-antigen-expressing-lymphoma-cells
#17
Emily C Piccione, Silvia Juarez, Jie Liu, Serena Tseng, Christine E Ryan, Cyndhavi Narayanan, Lijuan Wang, Kipp Weiskopf, Ravindra Majeti
Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20...
2015: MAbs
https://www.readbyqxmd.com/read/25775523/reprogramming-of-primary-human-philadelphia-chromosome-positive-b-cell-acute-lymphoblastic-leukemia-cells-into-nonleukemic-macrophages
#18
James Scott McClellan, Christopher Dove, Andrew J Gentles, Christine E Ryan, Ravindra Majeti
BCR-ABL1(+) precursor B-cell acute lymphoblastic leukemia (BCR-ABL1(+) B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. We hypothesized that overcoming this differentiation block by forcing cells to reprogram to the myeloid lineage would reduce the leukemogenicity of these cells. We found that primary human BCR-ABL1(+) B-ALL cells could be induced to reprogram into macrophage-like cells by exposure to myeloid differentiation-promoting cytokines in vitro or by transient expression of the myeloid transcription factor C/EBPα or PU...
March 31, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25728669/tuning-cytokine-receptor-signaling-by-re-orienting-dimer-geometry-with-surrogate-ligands
#19
Ignacio Moraga, Gerlinde Wernig, Stephan Wilmes, Vitalina Gryshkova, Christian P Richter, Wan-Jen Hong, Rahul Sinha, Feng Guo, Hyna Fabionar, Tom S Wehrman, Peter Krutzik, Samuel Demharter, Isabelle Plo, Irving L Weissman, Peter Minary, Ravindra Majeti, Stefan N Constantinescu, Jacob Piehler, K Christopher Garcia
Most cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity...
March 12, 2015: Cell
https://www.readbyqxmd.com/read/25599133/isocitrate-dehydrogenase-1-and-2-mutations-induce-bcl-2-dependence-in-acute-myeloid-leukemia
#20
Steven M Chan, Daniel Thomas, M Ryan Corces-Zimmerman, Seethu Xavy, Suchita Rastogi, Wan-Jen Hong, Feifei Zhao, Bruno C Medeiros, David A Tyvoll, Ravindra Majeti
Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1(R132H) mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models...
February 2015: Nature Medicine
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