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Ravindra Majeti

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https://www.readbyqxmd.com/read/28956530/multiplexed-genetic-engineering-of-human-hematopoietic-stem-and-progenitor-cells-using-crispr-cas9-and-aav6
#1
Rasmus O Bak, Daniel P Dever, Andreas Reinisch, David Cruz Hernandez, Ravindra Majeti, Matthew H Porteus
Precise and efficient manipulation of genes is crucial for understanding the molecular mechanisms that govern human hematopoiesis and for developing novel therapies for diseases of the blood and immune system. Current methods do not enable precise engineering of complex genotypes that can be easily tracked in a mixed population of cells. We describe a method to multiplex homologous recombination (HR) in human hematopoietic stem and progenitor cells and primary human T cells by combining rAAV6 donor delivery and the CRISPR/Cas9 system delivered as ribonucleoproteins (RNPs)...
September 28, 2017: ELife
https://www.readbyqxmd.com/read/28933777/generation-and-use-of-a-humanized-bone-marrow-ossicle-niche-for-hematopoietic-xenotransplantation-into-mice
#2
Andreas Reinisch, David Cruz Hernandez, Katharina Schallmoser, Ravindra Majeti
Xenotransplantation is frequently used to study normal and malignant hematopoiesis of human cells. However, conventional mouse xenotransplantation models lack essential human-specific bone-marrow (BM)-microenvironment-derived survival, proliferation, and self-renewal signals for engraftment of normal and malignant blood cells. As a consequence, many human leukemias and other hematologic disorders do not robustly engraft in these conventional models. Here, we describe a complete workflow for the generation of humanized ossicles with an accessible BM microenvironment that faithfully recapitulates normal BM niche morphology and function...
October 2017: Nature Protocols
https://www.readbyqxmd.com/read/28729405/superenhancer-analysis-defines-novel-epigenomic-subtypes-of-non-apl-aml-including-an-rar%C3%AE-dependency-targetable-by-sy-1425-a-potent-and-selective-rar%C3%AE-agonist
#3
Michael R McKeown, M Ryan Corces, Matthew L Eaton, Chris Fiore, Emily Lee, Jeremy T Lopez, Mei Wei Chen, Darren Smith, Steven M Chan, Julie L Koenig, Kathryn Austgen, Matthew G Guenther, David A Orlando, Jakob Lovén, Christian C Fritz, Ravindra Majeti
We characterized the enhancer landscape of 66 patients with acute myeloid leukemia (AML), identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their superenhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong SE at the retinoic acid receptor alpha (RARA) gene locus. The presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene)...
October 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28561042/systematic-discovery-of-mutation-specific-synthetic-lethals-by-mining-pan-cancer-human-primary-tumor-data
#4
Subarna Sinha, Daniel Thomas, Steven Chan, Yang Gao, Diede Brunen, Damoun Torabi, Andreas Reinisch, David Hernandez, Andy Chan, Erinn B Rankin, Rene Bernards, Ravindra Majeti, David L Dill
Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation-specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891 SL partners for 3,120 mutations, including known mutation-specific SL partners...
May 31, 2017: Nature Communications
https://www.readbyqxmd.com/read/28461409/optimizing-next-generation-aml-therapy-activity-of-mutant-idh2-inhibitor-ag-221-in-preclinical-models
#5
Daniel Thomas, Ravindra Majeti
AG-221 or enasidenib is a first-in-class selective inhibitor of mutated isocitrate dehydrogenase 2 (IDH2) with early demonstrated clinical efficacy in acute myeloid leukemia as a single agent, yet with persistence of mutant IDH2 clones. Two articles in this issue of Cancer Discovery provide further insight into the biological activity of AG-221 in promoting differentiation of IDH2-mutant cells and reversing aberrant DNA methylation over time, and demonstrating preclinical activity in combination with a targeted FLT3 kinase inhibitor to eliminate IDH2-mutant clones...
May 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28159741/biology-and-relevance-of-human-acute-myeloid-leukemia-stem-cells
#6
REVIEW
Daniel Thomas, Ravindra Majeti
Evidence of human acute myeloid leukemia stem cells (AML LSCs) was first reported nearly 2 decades ago through the identification of rare subpopulations of engrafting cells in xenotransplantation assays. These AML LSCs were shown to reside at the apex of a cellular hierarchy that initiates and maintains the disease, exhibiting properties of self-renewal, cell cycle quiescence, and chemoresistance. This cancer stem cell model offers an explanation for chemotherapy resistance and disease relapse and implies that approaches to treatment must eradicate LSCs for cure...
March 23, 2017: Blood
https://www.readbyqxmd.com/read/28089908/human-aml-ipscs-reacquire-leukemic-properties-after-differentiation-and-model-clonal-variation-of-disease
#7
Mark P Chao, Andrew J Gentles, Susmita Chatterjee, Feng Lan, Andreas Reinisch, M Ryan Corces, Seethu Xavy, Jinfeng Shen, Daniel Haag, Soham Chanda, Rahul Sinha, Rachel M Morganti, Toshinobu Nishimura, Mohamed Ameen, Haodi Wu, Marius Wernig, Joseph C Wu, Ravindra Majeti
Understanding the relative contributions of genetic and epigenetic abnormalities to acute myeloid leukemia (AML) should assist integrated design of targeted therapies. In this study, we generated induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements and found that they retained leukemic mutations but reset leukemic DNA methylation/gene expression patterns. AML-iPSCs lacked leukemic potential, but when differentiated into hematopoietic cells, they reacquired the ability to give rise to leukemia in vivo and reestablished leukemic DNA methylation/gene expression patterns, including an aberrant MLL signature...
March 2, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/27846387/sticking-it-to-the-niche-cd98-mediates-critical-adhesive-signals-in-aml
#8
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
#9
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 17, 2016: Nature
https://www.readbyqxmd.com/read/27796738/the-role-of-mutations-in-the-cohesin-complex-in-acute-myeloid-leukemia
#10
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...
January 2017: 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
#11
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...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27526324/lineage-specific-and-single-cell-chromatin-accessibility-charts-human-hematopoiesis-and-leukemia-evolution
#12
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
#13
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
#14
COMMENT
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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