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2. Potent and uniform fetal hemoglobin induction via base editing

Author

Mayuranathan, Thiyagaraj, Newby, Gregory A., Feng, Ruopeng, Yao, Yu, Mayberry, Kalin D., Lazzarotto, Cicera R., Li, Yichao, Levine, Rachel M., Nimmagadda, Nikitha, Dempsey, Erin, Kang, Guolian, Porter, Shaina N., Doerfler, Phillip A., Zhang, Jingjing, Jang, Yoonjeong, Chen, Jingjing, Bell, Henry W., Crossley, Merlin, Bhoopalan, Senthil Velan, Sharma, Akshay, Tisdale, John F., Pruett-Miller, Shondra M., Cheng, Yong, Tsai, Shengdar Q., Liu, David R., Weiss, Mitchell J., and Yen, Jonathan S.

Published
2023
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5. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice

Author

Everette, Kelcee A., Newby, Gregory A., Levine, Rachel M., Mayberry, Kalin, Jang, Yoonjeong, Mayuranathan, Thiyagaraj, Nimmagadda, Nikitha, Dempsey, Erin, Li, Yichao, Bhoopalan, Senthil Velan, Liu, Xiong, Davis, Jessie R., Nelson, Andrew T., Chen, Peter J., Sousa, Alexander A., Cheng, Yong, Tisdale, John F., Weiss, Mitchell J., Yen, Jonathan S., and Liu, David R.

Published
2023
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7. Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease

Author

Katta, Varun, O’Keefe, Kiera, Li, Yichao, Mayuranathan, Thiyagaraj, Lazzarotto, Cicera R., Wood, Rachael K., Levine, Rachel M., Powers, Alicia, Mayberry, Kalin, Manquen, Garret, Yao, Yu, Zhang, Jingjing, Jang, Yoonjeong, Nimmagadda, Nikitha, Dempsey, Erin A., Lee, GaHyun, Uchida, Naoya, Cheng, Yong, Fazio, Frank, Lockey, Tim, Meagher, Mike, Sharma, Akshay, Tisdale, John F., Zhou, Sheng, Yen, Jonathan S., Weiss, Mitchell J., and Tsai, Shengdar Q.

Published
2024
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8. ETV6 represses inflammatory response genes and regulates HSPC function during stress hematopoiesis in mice

Author

Bloom, Mackenzie, Oak, Ninad, Baskin-Doerfler, Rebekah, Feng, Ruopeng, Iacobucci, Ilaria, Baviskar, Pradyumna, Zhao, Xujie, Stroh, Alexa N., Li, Chunliang, Ozark, Patrick, Tillman, Heather S., Li, Yichao, Verbist, Katherine C., Albeituni, Sabrin, Scott, Danny C., King, Moeko T., McKinney-Freeman, Shannon L., Weiss, Mitchell J., Yang, Jun J., and Nichols, Kim E.

Published
2023
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12. Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells

Author

Lian, Xizhen, primary, Chatterjee, Sumanta, additional, Sun, Yehui, additional, Dilliard, Sean A., additional, Moore, Stephen, additional, Xiao, Yufen, additional, Bian, Xiaoyan, additional, Yamada, Kohki, additional, Sung, Yun-Chieh, additional, Levine, Rachel M., additional, Mayberry, Kalin, additional, John, Samuel, additional, Liu, Xiaoye, additional, Smith, Caroline, additional, Johnson, Lindsay T., additional, Wang, Xu, additional, Zhang, Cheng Cheng, additional, Liu, David R., additional, Newby, Gregory A., additional, Weiss, Mitchell J., additional, Yen, Jonathan S., additional, and Siegwart, Daniel J., additional

Published
2024
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14. Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

Author

Mamcarz, Ewelina, Zhou, Sheng, Lockey, Timothy, Abdelsamed, Hossam, Cross, Shane J, Kang, Guolian, Ma, Zhijun, Condori, Jose, Dowdy, Jola, Triplett, Brandon, Li, Chen, Maron, Gabriela, Aldave Becerra, Juan C, Church, Joseph A, Dokmeci, Elif, Love, James T, da Matta Ain, Ana C, van der Watt, Hedi, Tang, Xing, Janssen, William, Ryu, Byoung Y, De Ravin, Suk See, Weiss, Mitchell J, Youngblood, Benjamin, Long-Boyle, Janel R, Gottschalk, Stephen, Meagher, Michael M, Malech, Harry L, Puck, Jennifer M, Cowan, Morton J, and Sorrentino, Brian P

Subjects
Prevention, Transplantation, Regenerative Medicine, Rare Diseases, Genetics, Biotechnology, Vaccine Related, Pediatric, Hematology, Stem Cell Research, Gene Therapy, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, 6.2 Cellular and gene therapies, Antigens, Differentiation, T-Lymphocyte, B-Lymphocytes, Busulfan, Genetic Therapy, Genetic Vectors, Hematopoietic Stem Cell Transplantation, Humans, Immunoglobulin M, Infant, Interleukin Receptor Common gamma Subunit, Killer Cells, Natural, Lentivirus, Lymphocyte Count, Male, T-Lymphocytes, Transplantation Conditioning, X-Linked Combined Immunodeficiency Diseases, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundAllogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia.MethodsWe performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1.ResultsEight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven.ConclusionsLentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).

Published
2019

15. Mutation-specific signaling profiles and kinase inhibitor sensitivities of juvenile myelomonocytic leukemia revealed by induced pluripotent stem cells

Author

Tasian, Sarah K, Casas, Jessica A, Posocco, David, Gandre-Babbe, Shilpa, Gagne, Alyssa L, Liang, Ge, Loh, Mignon L, Weiss, Mitchell J, French, Deborah L, and Chou, Stella T

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Rare Diseases, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research, Cancer, Pediatric, Hematology, Clinical Research, Child, Humans, Induced Pluripotent Stem Cells, Leukemia, Myelomonocytic, Juvenile, Mutation, Neoplastic Stem Cells, Protein Kinase Inhibitors, Protein Kinases, Signal Transduction, Tumor Cells, Cultured, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
Abstract

Juvenile myelomonocytic leukemia (JMML) is an uncommon myeloproliferative neoplasm driven by Ras pathway mutations and hyperactive Ras/MAPK signaling. Outcomes for many children with JMML remain dismal with current standard-of-care cytoreductive chemotherapy and hematopoietic stem cell transplantation. We used patient-derived induced pluripotent stem cells (iPSCs) to characterize the signaling profiles and potential therapeutic vulnerabilities of PTPN11-mutant and CBL-mutant JMML. We assessed whether MEK, JAK, and PI3K/mTOR kinase inhibitors (i) could inhibit myeloproliferation and aberrant signaling in iPSC-derived hematopoietic progenitors with PTPN11 E76K or CBL Y371H mutations. We detected constitutive Ras/MAPK and PI3K/mTOR signaling in PTPN11 and CBL iPSC-derived myeloid cells. Activated signaling and growth of PTPN11 iPSCs were preferentially inhibited in vitro by the MEKi PD0325901 and trametinib. Conversely, JAK/STAT signaling was selectively activated in CBL iPSCs and abrogated by the JAKi momelotinib and ruxolitinib. The PI3Kδi idelalisib and mTORi rapamycin inhibited signaling and myeloproliferation in both PTPN11 and CBL iPSCs. These findings demonstrate differential sensitivity of PTPN11 iPSCs to MEKi and of CBL iPSCs to JAKi, but similar sensitivity to PI3Ki and mTORi. Clinical investigation of mutation-specific kinase inhibitor therapies in children with JMML may be warranted.

Published
2019

17. Endothelial alpha globin is a nitrite reductase

Author

Keller, IV, T. C. Stevenson, Lechauve, Christophe, Keller, Alexander S., Broseghini-Filho, Gilson Brás, Butcher, Joshua T., Askew Page, Henry R., Islam, Aditi, Tan, Zhe Yin, DeLalio, Leon J., Brooks, Steven, Sharma, Poonam, Hong, Kwangseok, Xu, Wenhao, Padilha, Alessandra Simão, Ruddiman, Claire A., Best, Angela K., Macal, Edgar, Kim-Shapiro, Daniel B., Christ, George, Yan, Zhen, Cortese-Krott, Miriam M., Ricart, Karina, Patel, Rakesh, Bender, Timothy P., Sonkusare, Swapnil K., Weiss, Mitchell J., Ackerman, Hans, Columbus, Linda, and Isakson, Brant E.

Published
2022
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18. Generation of a human Juvenile myelomonocytic leukemia iPSC line, CHOPi001-A, with a mutation in CBL

Author

Gagne, Alyssa L, Maguire, Jean Ann, Gandre-Babbe, Shilpa, Chou, Stella T, Tasian, Sarah K, Loh, Mignon L, Weiss, Mitchell J, Gadue, Paul, and French, Deborah L

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Pediatric Cancer, Stem Cell Research, Pediatric, Hematology, Rare Diseases, Cancer, Childhood Leukemia, Female, Humans, Induced Pluripotent Stem Cells, Infant, Leukemia, Myelomonocytic, Juvenile, Mutation, Medical and Health Sciences, Developmental Biology, Medical biotechnology, Oncology and carcinogenesis
Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative disorder of early childhood characterized by expansion of clonal myelomonocytic cells and hyperactive Ras/MAPK signaling. The disorder is caused by somatic and/or germline mutations in genes involved in the Ras/MAPK and JAK/STAT signaling pathways, including CBL. Here we describe the generation of an iPSC line with a homozygous CBL c.1111T->C (Y371H) mutation, designated CHOPJMML1854.

Published
2018

19. Ancestral β-globin gene haplotypes modify β-thalassemia severity in a mouse model

Author

Lechauve, Christophe, primary, Keith, Julia, additional, Fernandez, Alfonso G., additional, Khandros, Eugene, additional, Mayberry, Kalin, additional, Mayuranathan, Thiyagaraj, additional, Palmer, Lance E, additional, Qiu, Xiaohui, additional, Sheppard, Heather, additional, Telange, Rahul, additional, Herz, Hans-Martin, additional, and Weiss, Mitchell J., additional

Published
2024
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20. A polygenic score for acute vaso-occlusive pain in pediatric sickle cell disease

Author

Rampersaud, Evadnie, Kang, Guolian, Palmer, Lance E., Rashkin, Sara R., Wang, Shuoguo, Bi, Wenjian, Alberts, Nicole M., Anghelescu, Doralina, Barton, Martha, Birch, Kirby, Boulos, Nidal, Brandow, Amanda M., Brooke, Russell John, Chang, Ti-Cheng, Chen, Wenan, Cheng, Yong, Ding, Juan, Easton, John, Hodges, Jason R., Kanne, Celeste K., Levy, Shawn, Mulder, Heather, Patel, Ashwin P., Puri, Latika, Rosencrance, Celeste, Rusch, Michael, Sapkota, Yadav, Sioson, Edgar, Sharma, Akshay, Tang, Xing, Thrasher, Andrew, Wang, Winfred, Yao, Yu, Yasui, Yutaka, Yergeau, Donald, Hankins, Jane S., Sheehan, Vivien A., Downing, James R., Estepp, Jeremie H., Zhang, Jinghui, DeBaun, Michael, Wu, Gang, and Weiss, Mitchell J.

Published
2021
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22. Base editing of haematopoietic stem cells rescues sickle cell disease in mice

Author

Newby, Gregory A., Yen, Jonathan S., Woodard, Kaitly J., Mayuranathan, Thiyagaraj, Lazzarotto, Cicera R., Li, Yichao, Sheppard-Tillman, Heather, Porter, Shaina N., Yao, Yu, Mayberry, Kalin, Everette, Kelcee A., Jang, Yoonjeong, Podracky, Christopher J., Thaman, Elizabeth, Lechauve, Christophe, Sharma, Akshay, Henderson, Jordana M., Richter, Michelle F., Zhao, Kevin T., Miller, Shannon M., Wang, Tina, Koblan, Luke W., McCaffrey, Anton P., Tisdale, John F., Kalfa, Theodosia A., Pruett-Miller, Shondra M., Tsai, Shengdar Q., Weiss, Mitchell J., and Liu, David R.

Published
2021
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25. FBXO11-mediated proteolysis of BAHD1 relieves PRC2-dependent transcriptional repression in erythropoiesis

Author

Xu, Peng, Scott, Daniel C., Xu, Beisi, Yao, Yu, Feng, Ruopeng, Cheng, Li, Mayberry, Kalin, Wang, Yong-Dong, Bi, Wenjian, Palmer, Lance E., King, Moeko T., Wang, Hong, Li, Yuxin, Fan, Yiping, Alpi, Arno F., Li, Chunliang, Peng, Junmin, Papizan, James, Pruett-Miller, Shondra M., Spallek, Ria, Bassermann, Florian, Cheng, Yong, Schulman, Brenda A., and Weiss, Mitchell J.

Published
2021
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28. BCL11A enhancer-edited hematopoietic stem cells persist in rhesus monkeys without toxicity

Author

Demirci, Selami, Zeng, Jing, Wu, Yuxuan, Uchida, Naoya, Shen, Anne H., Pellin, Danilo, Gamer, Jackson, Yapundich, Morgan, Drysdale, Claire, Bonanno, Jasmine, Bonifacino, Aylin C., Krouse, Allen E., Linde, Nathaniel S., Engels, Theresa, Donahue, Robert E., Haro-Mora, Juan J., Leonard, Alexis, Nassehi, Tina, Luk, Kevin, Porter, Shaina N., Lazzarotto, Cicera R., Tsai, Shengdar Q., Weiss, Mitchell J., Pruett-Miller, Shondra M., Wolfe, Scot A., Bauer, Daniel E., and Tisdale, John F.

Subjects
Genetic engineering -- Research, Genetic research, Hematopoietic stem cells -- Genetic aspects -- Health aspects, Stem cell research, Stem cell transplantation -- Patient outcomes, Health care industry
Abstract

Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from patients with sickle cell disease (SCD) induces fetal hemoglobin (HbF) without detectable toxicity, as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer-edited HSPCs in 4 nonhuman primates. We used a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits persisted in peripheral blood (PB) and bone marrow (BM) for up to 101 weeks similarly for BCL11A enhancer- or control locus-targeted (AAV51-targeted) cells. Biallelic BCL11A enhancer editing resulted in robust [gamma]-globin induction, with the highest levels observed during stress erythropoiesis. Indels were evenly distributed across PB and BM lineages. Off-target edits were not observed. Nonhomologous end-joining repair alleles were enriched in engrafting HSCs. In summary, we found that edited HSCs can persist for at least 101 weeks after transplant and biallelic-edited HSCs provide substantial HbF levels in PB red blood cells, together supporting further clinical translation of this approach., Introduction The [beta]-hemoglobin (HBB) disorders, including sickle cell disease (SCD) and [beta]-thalassemia, are the most common single-gene inherited disorders, resulting in severe morbidity and mortality worldwide. The only curative therapeutic [...]

Published
2020
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29. Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells

Author

Giani, Felix C, Fiorini, Claudia, Wakabayashi, Aoi, Ludwig, Leif S, Salem, Rany M, Jobaliya, Chintan D, Regan, Stephanie N, Ulirsch, Jacob C, Liang, Ge, Steinberg-Shemer, Orna, Guo, Michael H, Esko, Tõnu, Tong, Wei, Brugnara, Carlo, Hirschhorn, Joel N, Weiss, Mitchell J, Zon, Leonard I, Chou, Stella T, French, Deborah L, Musunuru, Kiran, and Sankaran, Vijay G

Subjects
Medical Biotechnology, Biological Sciences, Biomedical and Clinical Sciences, Stem Cell Research - Nonembryonic - Non-Human, Genetics, Hematology, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research - Nonembryonic - Human, Stem Cell Research - Embryonic - Human, Stem Cell Research, Human Genome, Clinical Research, Biotechnology, Regenerative Medicine, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Underpinning research, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, 1.1 Normal biological development and functioning, Blood, Generic health relevance, CRISPR-Cas Systems, Cell Differentiation, Cytokines, Embryonic Stem Cells, Erythrocytes, Fetal Blood, Genetic Techniques, Genetic Variation, Genome, Human, Hematopoietic Stem Cells, Hemoglobins, Humans, Mutation, Pluripotent Stem Cells, Stem Cells, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Multipotent and pluripotent stem cells are potential sources for cell and tissue replacement therapies. For example, stem cell-derived red blood cells (RBCs) are a potential alternative to donated blood, but yield and quality remain a challenge. Here, we show that application of insight from human population genetic studies can enhance RBC production from stem cells. The SH2B3 gene encodes a negative regulator of cytokine signaling and naturally occurring loss-of-function variants in this gene increase RBC counts in vivo. Targeted suppression of SH2B3 in primary human hematopoietic stem and progenitor cells enhanced the maturation and overall yield of in-vitro-derived RBCs. Moreover, inactivation of SH2B3 by CRISPR/Cas9 genome editing in human pluripotent stem cells allowed enhanced erythroid cell expansion with preserved differentiation. Our findings therefore highlight the potential for combining human genome variation studies with genome editing approaches to improve cell and tissue production for regenerative medicine.

Published
2016

30. Genome editing of HBG1 and HBG2 to induce fetal hemoglobin

Author

Métais, Jean-Yves, Doerfler, Phillip A., Mayuranathan, Thiyagaraj, Bauer, Daniel E., Fowler, Stephanie C., Hsieh, Matthew M., Katta, Varun, Keriwala, Sagar, Lazzarotto, Cicera R., Luk, Kevin, Neel, Michael D., Perry, S. Scott, Peters, Samuel T., Porter, Shaina N., Ryu, Byoung Y., Sharma, Akshay, Shea, Devlin, Tisdale, John F., Uchida, Naoya, Wolfe, Scot A., Woodard, Kaitly J., Wu, Yuxuan, Yao, Yu, Zeng, Jing, Pruett-Miller, Shondra, Tsai, Shengdar Q., and Weiss, Mitchell J.

Published
2019
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33. UBE2O remodels the proteome during terminal erythroid differentiation

Author

Nguyen, Anthony T., Prado, Miguel A., Schmidt, Paul J., Sendamarai, Anoop K., Wilson-Grady, Joshua T., Min, Mingwei, Campagna, Dean R., Tian, Geng, Shi, Yuan, Dederer, Verena, Kawan, Mona, Kuehnle, Nathalie, Paulo, Joao A., Yao, Yu, Weiss, Mitchell J., Justice, Monica J., Gygi, Steven P., Fleming, Mark D., and Finley, Daniel

Published
2017

34. Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes

Author

Xiang, Guanjue, primary, He, Xi, additional, Giardine, Belinda M., additional, Weaver, Kathryn J., additional, Taylor, Dylan J., additional, McCoy, Rajiv C., additional, Jansen, Camden, additional, Keller, Cheryl A., additional, Wixom, Alexander Q., additional, Cockburn, April, additional, Miller, Amber, additional, Qi, Qian, additional, He, Yanghua, additional, Li, Yichao, additional, Lichtenberg, Jens, additional, Heuston, Elisabeth F., additional, Anderson, Stacie M., additional, Luan, Jing, additional, Vermunt, Marit W., additional, Yue, Feng, additional, Sauria, Michael E.G., additional, Schatz, Michael C., additional, Taylor, James, additional, Göttgens, Berthold, additional, Hughes, Jim R., additional, Higgs, Douglas R., additional, Weiss, Mitchell J., additional, Cheng, Yong, additional, Blobel, Gerd A., additional, Bodine, David, additional, Zhang, Yu, additional, Li, Qunhua, additional, Mahony, Shaun, additional, and Hardison, Ross C., additional

Published
2023
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35. Data from St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem

Author

McLeod, Clay, primary, Gout, Alexander M., primary, Zhou, Xin, primary, Thrasher, Andrew, primary, Rahbarinia, Delaram, primary, Brady, Samuel W., primary, Macias, Michael, primary, Birch, Kirby, primary, Finkelstein, David, primary, Sunny, Jobin, primary, Mudunuri, Rahul, primary, Orr, Brent A., primary, Treadway, Madison, primary, Davidson, Bob, primary, Ard, Tracy K., primary, Chiao, Arthur, primary, Swistak, Andrew, primary, Wiggins, Stephanie, primary, Foy, Scott, primary, Wang, Jian, primary, Sioson, Edgar, primary, Wang, Shuoguo, primary, Michael, J. Robert, primary, Liu, Yu, primary, Ma, Xiaotu, primary, Patel, Aman, primary, Edmonson, Michael N., primary, Wilkinson, Mark R., primary, Frantz, Andrew M., primary, Chang, Ti-Cheng, primary, Tian, Liqing, primary, Lei, Shaohua, primary, Islam, S.M. Ashiqul, primary, Meyer, Christopher, primary, Thangaraj, Naina, primary, Tater, Pamella, primary, Kandali, Vijay, primary, Ma, Singer, primary, Nguyen, Tuan, primary, Serang, Omar, primary, McGuire, Irina, primary, Robison, Nedra, primary, Gentry, Darrell, primary, Tang, Xing, primary, Palmer, Lance E., primary, Wu, Gang, primary, Suh, Ed, primary, Tanner, Leigh, primary, McMurry, James, primary, Lear, Matthew, primary, Pappo, Alberto S., primary, Wang, Zhaoming, primary, Wilson, Carmen L., primary, Cheng, Yong, primary, Meshinchi, Soheil, primary, Alexandrov, Ludmil B., primary, Weiss, Mitchell J., primary, Armstrong, Gregory T., primary, Robison, Leslie L., primary, Yasui, Yutaka, primary, Nichols, Kim E., primary, Ellison, David W., primary, Bangur, Chaitanya, primary, Mullighan, Charles G., primary, Baker, Suzanne J., primary, Dyer, Michael A., primary, Miller, Geralyn, primary, Newman, Scott, primary, Rusch, Michael, primary, Daly, Richard, primary, Perry, Keith, primary, Downing, James R., primary, and Zhang, Jinghui, primary

Published
2023
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36. Supplementary Tables from St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem

Author

McLeod, Clay, primary, Gout, Alexander M., primary, Zhou, Xin, primary, Thrasher, Andrew, primary, Rahbarinia, Delaram, primary, Brady, Samuel W., primary, Macias, Michael, primary, Birch, Kirby, primary, Finkelstein, David, primary, Sunny, Jobin, primary, Mudunuri, Rahul, primary, Orr, Brent A., primary, Treadway, Madison, primary, Davidson, Bob, primary, Ard, Tracy K., primary, Chiao, Arthur, primary, Swistak, Andrew, primary, Wiggins, Stephanie, primary, Foy, Scott, primary, Wang, Jian, primary, Sioson, Edgar, primary, Wang, Shuoguo, primary, Michael, J. Robert, primary, Liu, Yu, primary, Ma, Xiaotu, primary, Patel, Aman, primary, Edmonson, Michael N., primary, Wilkinson, Mark R., primary, Frantz, Andrew M., primary, Chang, Ti-Cheng, primary, Tian, Liqing, primary, Lei, Shaohua, primary, Islam, S.M. Ashiqul, primary, Meyer, Christopher, primary, Thangaraj, Naina, primary, Tater, Pamella, primary, Kandali, Vijay, primary, Ma, Singer, primary, Nguyen, Tuan, primary, Serang, Omar, primary, McGuire, Irina, primary, Robison, Nedra, primary, Gentry, Darrell, primary, Tang, Xing, primary, Palmer, Lance E., primary, Wu, Gang, primary, Suh, Ed, primary, Tanner, Leigh, primary, McMurry, James, primary, Lear, Matthew, primary, Pappo, Alberto S., primary, Wang, Zhaoming, primary, Wilson, Carmen L., primary, Cheng, Yong, primary, Meshinchi, Soheil, primary, Alexandrov, Ludmil B., primary, Weiss, Mitchell J., primary, Armstrong, Gregory T., primary, Robison, Leslie L., primary, Yasui, Yutaka, primary, Nichols, Kim E., primary, Ellison, David W., primary, Bangur, Chaitanya, primary, Mullighan, Charles G., primary, Baker, Suzanne J., primary, Dyer, Michael A., primary, Miller, Geralyn, primary, Newman, Scott, primary, Rusch, Michael, primary, Daly, Richard, primary, Perry, Keith, primary, Downing, James R., primary, and Zhang, Jinghui, primary

Published
2023
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37. Supplementary Data from St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem

Author

McLeod, Clay, primary, Gout, Alexander M., primary, Zhou, Xin, primary, Thrasher, Andrew, primary, Rahbarinia, Delaram, primary, Brady, Samuel W., primary, Macias, Michael, primary, Birch, Kirby, primary, Finkelstein, David, primary, Sunny, Jobin, primary, Mudunuri, Rahul, primary, Orr, Brent A., primary, Treadway, Madison, primary, Davidson, Bob, primary, Ard, Tracy K., primary, Chiao, Arthur, primary, Swistak, Andrew, primary, Wiggins, Stephanie, primary, Foy, Scott, primary, Wang, Jian, primary, Sioson, Edgar, primary, Wang, Shuoguo, primary, Michael, J. Robert, primary, Liu, Yu, primary, Ma, Xiaotu, primary, Patel, Aman, primary, Edmonson, Michael N., primary, Wilkinson, Mark R., primary, Frantz, Andrew M., primary, Chang, Ti-Cheng, primary, Tian, Liqing, primary, Lei, Shaohua, primary, Islam, S.M. Ashiqul, primary, Meyer, Christopher, primary, Thangaraj, Naina, primary, Tater, Pamella, primary, Kandali, Vijay, primary, Ma, Singer, primary, Nguyen, Tuan, primary, Serang, Omar, primary, McGuire, Irina, primary, Robison, Nedra, primary, Gentry, Darrell, primary, Tang, Xing, primary, Palmer, Lance E., primary, Wu, Gang, primary, Suh, Ed, primary, Tanner, Leigh, primary, McMurry, James, primary, Lear, Matthew, primary, Pappo, Alberto S., primary, Wang, Zhaoming, primary, Wilson, Carmen L., primary, Cheng, Yong, primary, Meshinchi, Soheil, primary, Alexandrov, Ludmil B., primary, Weiss, Mitchell J., primary, Armstrong, Gregory T., primary, Robison, Leslie L., primary, Yasui, Yutaka, primary, Nichols, Kim E., primary, Ellison, David W., primary, Bangur, Chaitanya, primary, Mullighan, Charles G., primary, Baker, Suzanne J., primary, Dyer, Michael A., primary, Miller, Geralyn, primary, Newman, Scott, primary, Rusch, Michael, primary, Daly, Richard, primary, Perry, Keith, primary, Downing, James R., primary, and Zhang, Jinghui, primary

Published
2023
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39. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

Author

Leiding, Jennifer W., primary, Vogel, Tiphanie P., additional, Santarlas, Valentine G.J., additional, Mhaskar, Rahul, additional, Smith, Madison R., additional, Carisey, Alexandre, additional, Vargas-Hernández, Alexander, additional, Silva-Carmona, Manuel, additional, Heeg, Maximilian, additional, Rensing-Ehl, Anne, additional, Neven, Bénédicte, additional, Hadjadj, Jérôme, additional, Hambleton, Sophie, additional, Ronan Leahy, Timothy, additional, Meesilpavikai, Kornvalee, additional, Cunningham-Rundles, Charlotte, additional, Dutmer, Cullen M., additional, Sharapova, Svetlana O., additional, Taskinen, Mervi, additional, Chua, Ignatius, additional, Hague, Rosie, additional, Klemann, Christian, additional, Kostyuchenko, Larysa, additional, Morio, Tomohiro, additional, Thatayatikom, Akaluck, additional, Ozen, Ahmet, additional, Scherbina, Anna, additional, Bauer, Cindy S., additional, Flanagan, Sarah E., additional, Gambineri, Eleonora, additional, Giovannini-Chami, Lisa, additional, Heimall, Jennifer, additional, Sullivan, Kathleen E., additional, Allenspach, Eric, additional, Romberg, Neil, additional, Deane, Sean G., additional, Prince, Benjamin T., additional, Rose, Melissa J., additional, Bohnsack, John, additional, Mousallem, Talal, additional, Jesudas, Rohith, additional, Santos Vilela, Maria Marluce Dos, additional, O’Sullivan, Michael, additional, Pachlopnik Schmid, Jana, additional, Průhová, Štěpánka, additional, Klocperk, Adam, additional, Rees, Matthew, additional, Su, Helen, additional, Bahna, Sami, additional, Baris, Safa, additional, Bartnikas, Lisa M., additional, Chang Berger, Amy, additional, Briggs, Tracy A., additional, Brothers, Shannon, additional, Bundy, Vanessa, additional, Chan, Alice Y., additional, Chandrakasan, Shanmuganathan, additional, Christiansen, Mette, additional, Cole, Theresa, additional, Cook, Matthew C., additional, Desai, Mukesh M., additional, Fischer, Ute, additional, Fulcher, David A., additional, Gallo, Silvanna, additional, Gauthier, Amelie, additional, Gennery, Andrew R., additional, Gonçalo Marques, José, additional, Gottrand, Frédéric, additional, Grimbacher, Bodo, additional, Grunebaum, Eyal, additional, Haapaniemi, Emma, additional, Hämäläinen, Sari, additional, Heiskanen, Kaarina, additional, Heiskanen-Kosma, Tarja, additional, Hoffman, Hal M., additional, Gonzalez-Granado, Luis Ignacio, additional, Guerrerio, Anthony L., additional, Kainulainen, Leena, additional, Kumar, Ashish, additional, Lawrence, Monica G., additional, Levin, Carina, additional, Martelius, Timi, additional, Neth, Olaf, additional, Olbrich, Peter, additional, Palma, Alejandro, additional, Patel, Niraj C., additional, Pozos, Tamara, additional, Preece, Kahn, additional, Lugo Reyes, Saúl Oswaldo, additional, Russell, Mark A., additional, Schejter, Yael, additional, Seroogy, Christine, additional, Sinclair, Jan, additional, Skevofilax, Effie, additional, Suan, Daniel, additional, Suez, Daniel, additional, Szabolcs, Paul, additional, Velasco, Helena, additional, Warnatz, Klaus, additional, Walkovich, Kelly, additional, Worth, Austen, additional, Seppänen, Mikko R.J., additional, Torgerson, Troy R., additional, Sogkas, Georgios, additional, Ehl, Stephan, additional, Tangye, Stuart G., additional, Cooper, Megan A., additional, Milner, Joshua D., additional, Forbes Satter, Lisa R., additional, Aleshkevich, Svetlana, additional, Allende, Luis M., additional, Atkinson, T. Prescott, additional, Atschekzei, Faranaz, additional, Aydemir, Sezin, additional, Aygunes, Utku, additional, Barlogis, Vincent, additional, Baumann, Ulrich, additional, Belko, John, additional, Bezrodnik, Liliana, additional, Biebl, Ariane, additional, Broderick, Lori, additional, Bunin, Nancy J., additional, Caldirola, Maria Soledad, additional, Castelle, Martin, additional, Celmeli, Fatih, additional, Charbonnier, Louis-Marie, additional, Chatila, Talal A., additional, Chellapandian, Deepak, additional, Cokugras, Haluk, additional, Conlon, Niall, additional, Cox, Fionnuala, additional, Crickx, Etienne, additional, Dalgic, Buket, additional, ASH Dalm, Virgil, additional, Danielian, Silvia, additional, Dominguez-Pinilla, Nerea, additional, Dujovny, Tal, additional, Ebbo, Mikael, additional, Eken, Ahmet, additional, Esty, Brittany, additional, Fabre, Alexandre, additional, Fischer, Alain, additional, Hannibal, Mark, additional, Huppert, Laura, additional, Ikeda, Marc D., additional, Jolles, Stephen, additional, Jolly, Kent W., additional, Jones, Neil, additional, Kanariou, Maria, additional, Karakoc-Aydiner, Elif, additional, Karamantziani, Theoni, additional, Kelaidi, Charikleia, additional, Keogan, Mary, additional, Pac Kisaarslan, Ayşenur, additional, Kiykim, Ayca, additional, Kotsonis, Kosmas, additional, Kuzmenko, Natalia, additional, Leroy, Sylvie, additional, Lianou, Dimitra, additional, Longhurst, Hilary, additional, Lorenz, Myriam Ricarda, additional, Maffucci, Patrick, additional, Manson, Ania, additional, Marchal, Sarah, additional, Malphettes, Marion, additional, Marega, Lia Furlaneto, additional, Mauracher, Andrea A., additional, Miller, Holly, additional, Mombourquette, Joy, additional, Morgan, Noel G., additional, Mukhina, Anna, additional, Nathalie, Aladjidi, additional, Nelken, Brigitte, additional, Nolan, David, additional, Norlin, Anna-Carin, additional, Oleastro, Matias, additional, Ozcan, Alper, additional, Pasquet, Marlene, additional, Pegler, José Roberto, additional, Picard, Capucine, additional, Polychronopoulou, Sophia, additional, Quartier, Pierre, additional, Quesada, Juan Francisco, additional, Ramakers, Jan, additional, Randall, Katrina L., additional, Rao, V. Koneti, additional, Remiker, Allison, additional, Resin, Geraldine, additional, Richmond, Peter, additional, Rieux-Laucat, Frederic, additional, Rodina, Yulia, additional, Rohrlich, Pierre, additional, Sachs, Johnathan, additional, Sakovich, Inga, additional, Santarlas, Christopher, additional, Sari, Sinan, additional, Sawicki, Gregory, additional, Schauer, Uwe, additional, Scheffler Mendoza, Selma C., additional, Schvetz, Oksana, additional, Schmidt, Reinhold Ernst, additional, Schwarz, Klaus, additional, Sediva, Anna, additional, Sinclair, Kyle, additional, Slatter, Mary, additional, Sleasman, John, additional, Stergiou, Katerina, additional, Suratannon, Narissara, additional, Tanita, Kay, additional, Thompson, Grace, additional, Travis, Stephen, additional, Trojan, Timothy, additional, Tsinti, Maria, additional, Unal, Ekrem, additional, Urdinez, Luciano, additional, Vazquez-Gomez, Felisa, additional, Villa, Mariana, additional, Weinrich, Michael, additional, Weiss, Mitchell J., additional, Wright, Benjamin, additional, Yilmaz, Ebru, additional, Zachova, Radana, additional, and Zhang, Yu, additional

Published
2023
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41. Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes

Author

Xiang, Guanjue, He, Xi, Giardine, Belinda M., Isaac, Kathryn J., Taylor, Dylan J., McCoy, Rajiv C., Jansen, Camden, Keller, Cheryl A., Wixom, Alexander Q., Cockburn, April, Miller, Amber, Qi, Qian, He, Yanghua, Li, Yichao, Lichtenberg, Jens, Heuston, Elisabeth F., Anderson, Stacie M., Luan, Jing, Vermunt, Marit W., Yue, Feng, Sauria, Michael E.G., Schatz, Michael C., Taylor, James, Go¨ttgens, Berthold, Hughes, Jim R., Higgs, Douglas R., Weiss, Mitchell J., Cheng, Yong, Blobel, Gerd A., Bodine, David M., Zhang, Yu, Li, Qunhua, Mahony, Shaun, and Hardison, Ross C.

Abstract

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state regulatory potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbor distinctive transcription factor binding motifs that are similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we show that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Published
2024
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44. Genetic therapies for the first molecular disease

Author

Doerfler, Phillip A., Sharma, Akshay, Porter, Jerlym S., Zheng, Yan, Tisdale, John F., and Weiss, Mitchell J.

Subjects
Sickle cell anemia -- Genetic aspects -- Development and progression -- Care and treatment, Hematopoietic stem cells -- Transplantation, Genotype -- Health aspects, Health care industry
Abstract

Sickle cell disease (SCD) is a monogenic disorder characterized by recurrent episodes of severe bone pain, multi-organ failure, and early mortality. Although medical progress over the past several decades has improved clinical outcomes and offered cures for many affected individuals living in high-income countries, most SCD patients still experience substantial morbidity and premature death. Emerging technologies to manipulate somatic cell genomes and insights into the mechanisms of developmental globin gene regulation are generating potentially transformative approaches to cure SCD by autologous hematopoietic stem cell (HSC) transplantation. Key components of current approaches include ethical informed consent, isolation of patient HSCs, in vitro genetic modification of HSCs to correct the SCD mutation or circumvent its damaging effects, and reinfusion of the modified HSCs following myelotoxic bone marrow conditioning. Successful integration of these components into effective therapies requires interdisciplinary collaborations between laboratory researchers, clinical caregivers, and patients. Here we summarize current knowledge and research challenges for each key component, emphasizing that the best approaches have yet to be developed., Historical perspectives Studies of sickle cell disease (SCD), a life-threatening, multisystem genetic blood disorder that affects approximately 100,000 Americans and millions worldwide, have driven many advances in science and medicine. [...]

Published
2021
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45. Multiplex Base Editing to Protect from CD33-Directed Therapy: Implications for Immune and Gene Therapy

Author

Borot, Florence, primary, Humbert, Olivier, additional, Newby, Gregory A, additional, Fields, Emily, additional, Kohli, Sajeev, additional, Radtke, Stefan, additional, Laszlo, George S., additional, Mayuranathan, Thiyagaraj, additional, Ali, Abdullah Mahmood, additional, Weiss, Mitchell J., additional, Yen, Jonathan S., additional, Walter, Roland B., additional, Liu, David R., additional, Mukherjee, Siddhartha, additional, and Kiem, Hans-Peter, additional

Published
2023
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46. An RPS19-edited model for Diamond-Blackfan anemia reveals TP53-dependent impairment of hematopoietic stem cell activity

Author

Bhoopalan, Senthil Velan, primary, Yen, Jonathan S., additional, Mayuranathan, Thiyagaraj, additional, Mayberry, Kalin D., additional, Yao, Yu, additional, Lillo Osuna, Maria Angeles, additional, Jang, Yoonjeong, additional, Liyanage, Janaka S.S., additional, Blanc, Lionel, additional, Ellis, Steven R., additional, Wlodarski, Marcin W., additional, and Weiss, Mitchell J., additional

Published
2023
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47. Forced enhancer-promoter rewiring to alter gene expression in animal models

Author

Peslak, Scott A., primary, Demirci, Selami, additional, Chandra, Vemika, additional, Ryu, Byoung, additional, Bhardwaj, Saurabh K., additional, Jiang, Jing, additional, Rupon, Jeremy W., additional, Throm, Robert E., additional, Uchida, Naoya, additional, Leonard, Alexis, additional, Essawi, Khaled, additional, Bonifacino, Aylin C., additional, Krouse, Allen E., additional, Linde, Nathaniel S., additional, Donahue, Robert E., additional, Ferrara, Francesca, additional, Wielgosz, Matthew, additional, Abdulmalik, Osheiza, additional, Hamagami, Nicole, additional, Germino-Watnick, Paula, additional, Le, Anh, additional, Chu, Rebecca, additional, Hinds, Malikiya, additional, Weiss, Mitchell J., additional, Tong, Wei, additional, Tisdale, John F., additional, and Blobel, Gerd A., additional

Published
2023
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48. Genetic regulation of fetal hemoglobin across global populations

Author

Cato, Liam D, Li, Rick, Lu, Henry Y, Yu, Fulong, Wissman, Mariel, Mkumbe, Baraka S, Ekwattanakit, Supachai, Deelen, Patrick, Mwita, Liberata, Sangeda, Raphael Zozimus, Suksangpleng, Thidarat, Riolueang, Suchada, Bronson, Paola G, Paul, Dirk S, Kawabata, Emily, Astle, William J, Aguet, Francois, Ardlie, Kristin, Lopez de Lapuente Portilla, Aitzkoa, Kang, Guolian, Zhang, Yingze, Nouraie, Seyed Mehdi, Gordeuk, Victor R, Gladwin, Mark T, Garrett, Melanie E, Ashley-Koch, Allison, Telen, Marilyn J, Custer, Brian, Kelly, Shannon, DINARDO, CARLA, Sabino, Ester Cerdeira, Loureiro, Paula, Carneiro-Proietti, Anna Barbara, Maximo, Claudia, Mendez, Adriana, Hammerer-Lercher, Angelika, Sheehan, Vivien A, Weiss, Mitchell J, Franke, Lude, Nilsson, Bjorn, Butterworth, Adam S, Viprakasit, Vip, Nkya, Siana, and Sankaran, Vijay G.

Subjects
Article
Abstract

Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs in vivo. We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied BCL11A and HBS1L-MYB loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the HBB locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and β-thalassemia.

Published
2023

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