12 results on '"Hema Preethi"'
Search Results
2. Supplementary Figure legends from Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
- Author
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H. Phillip Koeffler, Henry Yang, Lee-Yung Shih, Seishi Ogawa, Der-Cherng Liang, Satoru Miyano, Steven M. Kornblau, Hagop M. Kantarjian, Michael Lill, Hema Preethi, Lucia Torres Fernández, Masashi Sanada, Vikas Madan, Li-Zhen Liu, Su-Lin Lim, Liang Xu, Yan-Yi Jiang, Manoj Garg, De-Chen Lin, Xin-Yi Loh, Jin-Fen Xiao, Yasunobu Nagata, Norihiko Kawamata, Allen Eng Juh Yeoh, Anand Mayakonda Thippeswamy, Wenwen Chien, Kar-Tong Tan, Qiao-Yang Sun, and Ling-Wen Ding
- Abstract
Legends for Supplementary Figures
- Published
- 2023
3. Data from Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
- Author
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H. Phillip Koeffler, Henry Yang, Lee-Yung Shih, Seishi Ogawa, Der-Cherng Liang, Satoru Miyano, Steven M. Kornblau, Hagop M. Kantarjian, Michael Lill, Hema Preethi, Lucia Torres Fernández, Masashi Sanada, Vikas Madan, Li-Zhen Liu, Su-Lin Lim, Liang Xu, Yan-Yi Jiang, Manoj Garg, De-Chen Lin, Xin-Yi Loh, Jin-Fen Xiao, Yasunobu Nagata, Norihiko Kawamata, Allen Eng Juh Yeoh, Anand Mayakonda Thippeswamy, Wenwen Chien, Kar-Tong Tan, Qiao-Yang Sun, and Ling-Wen Ding
- Abstract
Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. Cancer Res; 77(2); 390–400. ©2016 AACR.
- Published
- 2023
4. Supplementary Fig 4 from Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
- Author
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H. Phillip Koeffler, Henry Yang, Lee-Yung Shih, Seishi Ogawa, Der-Cherng Liang, Satoru Miyano, Steven M. Kornblau, Hagop M. Kantarjian, Michael Lill, Hema Preethi, Lucia Torres Fernández, Masashi Sanada, Vikas Madan, Li-Zhen Liu, Su-Lin Lim, Liang Xu, Yan-Yi Jiang, Manoj Garg, De-Chen Lin, Xin-Yi Loh, Jin-Fen Xiao, Yasunobu Nagata, Norihiko Kawamata, Allen Eng Juh Yeoh, Anand Mayakonda Thippeswamy, Wenwen Chien, Kar-Tong Tan, Qiao-Yang Sun, and Ling-Wen Ding
- Abstract
Supplementary Fig. 4. p53 pathway is dysregulated in ALL.
- Published
- 2023
5. Supplementary Fig 2 from Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
- Author
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H. Phillip Koeffler, Henry Yang, Lee-Yung Shih, Seishi Ogawa, Der-Cherng Liang, Satoru Miyano, Steven M. Kornblau, Hagop M. Kantarjian, Michael Lill, Hema Preethi, Lucia Torres Fernández, Masashi Sanada, Vikas Madan, Li-Zhen Liu, Su-Lin Lim, Liang Xu, Yan-Yi Jiang, Manoj Garg, De-Chen Lin, Xin-Yi Loh, Jin-Fen Xiao, Yasunobu Nagata, Norihiko Kawamata, Allen Eng Juh Yeoh, Anand Mayakonda Thippeswamy, Wenwen Chien, Kar-Tong Tan, Qiao-Yang Sun, and Ling-Wen Ding
- Abstract
Supplementary Fig. 2. Mutations found in the ASXL family of genes.
- Published
- 2023
6. Supplementary Fig 1 from Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
- Author
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H. Phillip Koeffler, Henry Yang, Lee-Yung Shih, Seishi Ogawa, Der-Cherng Liang, Satoru Miyano, Steven M. Kornblau, Hagop M. Kantarjian, Michael Lill, Hema Preethi, Lucia Torres Fernández, Masashi Sanada, Vikas Madan, Li-Zhen Liu, Su-Lin Lim, Liang Xu, Yan-Yi Jiang, Manoj Garg, De-Chen Lin, Xin-Yi Loh, Jin-Fen Xiao, Yasunobu Nagata, Norihiko Kawamata, Allen Eng Juh Yeoh, Anand Mayakonda Thippeswamy, Wenwen Chien, Kar-Tong Tan, Qiao-Yang Sun, and Ling-Wen Ding
- Abstract
Supplementary Fig. 1. Mutational spectrum of pediatric ALL.
- Published
- 2023
7. Supplementary Tables from Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
- Author
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H. Phillip Koeffler, Henry Yang, Lee-Yung Shih, Seishi Ogawa, Der-Cherng Liang, Satoru Miyano, Steven M. Kornblau, Hagop M. Kantarjian, Michael Lill, Hema Preethi, Lucia Torres Fernández, Masashi Sanada, Vikas Madan, Li-Zhen Liu, Su-Lin Lim, Liang Xu, Yan-Yi Jiang, Manoj Garg, De-Chen Lin, Xin-Yi Loh, Jin-Fen Xiao, Yasunobu Nagata, Norihiko Kawamata, Allen Eng Juh Yeoh, Anand Mayakonda Thippeswamy, Wenwen Chien, Kar-Tong Tan, Qiao-Yang Sun, and Ling-Wen Ding
- Abstract
Supplementary Table 1. Samples used for whole exome and targeted sequencing. Supplementary Table 2. Clinical information of patients. Supplementary Table 3. 560 Genes screened in the targeted sequencing. Supplementary Table 4. Sequences of shRNA or CRISPR-Cas9 sgRNA used in this study. Supplementary Table 5. Sequences of real-time PCR primers used in this study. Supplementary Table 6. Sequences of primers used for Sanger validation of CRISPR-Cas9 indel. Supplementary Table 7. Mutations of KRAS identified in this study have been found in a variety of cancers. Supplementary Table 8. Mutations of PTPN11 in other cancers occurring in the same location as in our ALL cohort. Supplementary Table 9. Recurrent mutation sites of FLT3 in different cancers. Supplementary Table 10. Cell lines or cancer samples harboring either E1099K or T1150A hotspot mutation of WHSC1. Supplementary Table 11. R1446 mutations of CREBBP recurrently occurred in a variety of cancers. Supplementary Table 12. Mutational hotspot (D1399) of EP300 occurring in other cancers occurring in the same location as in our ALL cohort.Supplementary Table 13. Rare mutations occurring in our ALL cohort (mutated in one individual each), but these mutations have been recurrently documented in the COSMIC cancer mutations database. Supplementary Table 14. Mutations of genes involved in DNA repair pathway in relapse samples.
- Published
- 2023
8. NAb-seq: an accurate, rapid, and cost-effective method for antibody long-read sequencing in hybridoma cell lines and single B cells
- Author
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Stephen Nutt, Rachel Uren, Hema Preethi Subas Satish, Ruth Kluck, Kathleen Zeglinski, Matthew Ritchie, and Quentin Gouil
- Subjects
Mice ,Hybridomas ,Cost-Benefit Analysis ,Immunology ,Animals ,Antibodies, Monoclonal ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,Immunology and Allergy ,Rabbits ,Cell Line ,Rats - Abstract
Despite their common use in research, monoclonal antibodies are currently not systematically sequenced. This can lead to issues with reproducibility and the occasional loss of antibodies with loss of cell lines. Hybridoma cell lines have been the primary means of generating monoclonal antibodies from immunized animals, including mice, rats, rabbits, and alpacas. Excluding therapeutic antibodies, few hybridoma-derived antibody sequences are known. Sanger sequencing has been "the gold standard" for antibody gene sequencing, but this method relies on the availability of species-specific degenerate primer sets for amplification of light and heavy antibody genes and it requires lengthy and expensive cDNA preparation. Here, we leveraged recent improvements in long-read Oxford Nanopore Technologies (ONT) sequencing to develop Nanopore Antibody sequencing (NAb-seq): a three-day, species-independent, and cost-effective workflow to characterize paired full-length immunoglobulin light- and heavy-chain genes from hybridoma cell lines. When compared to Sanger sequencing of two hybridoma cell lines, long-read ONT sequencing was highly accurate, reliable, and amenable to high throughput. We further show that the method is applicable to single cells, allowing efficient antibody discovery in rare populations such as memory B cells. In summary, NAb-seq promises to accelerate identification and validation of hybridoma antibodies as well as antibodies from single B cells used in research, diagnostics, and therapeutics.
- Published
- 2022
9. NAb-seq: an accurate, rapid and cost-effective method for antibody long-read sequencing in hybridoma cell lines and single B cells
- Author
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Hema Preethi Subas Satish, Kathleen Zeglinski, Rachel T. Uren, Stephen L. Nutt, Matthew E. Ritchie, Quentin Gouil, and Ruth M. Kluck
- Abstract
Despite their common use in research, monoclonal antibodies are currently not systematically sequenced. This can lead to issues with reproducibility and the occasional loss of antibodies with loss of cell lines. Hybridoma cell lines have been the primary means of generating monoclonal antibodies from immunized animals including mice, rats, rabbits and alpacas. Excluding therapeutic antibodies, few hybridoma-derived antibody sequences are known. Sanger sequencing has been “the gold standard” for antibody gene sequencing but relies on the availability of species-specific degenerate primer sets for amplification of light and heavy antibody genes, in addition to lengthy and expensive cDNA preparation. Here we leveraged recent improvements in long-read Oxford Nanopore Technologies (ONT) sequencing to develop NAb-seq: a three-day, species-independent, and cost-effective workflow to characterize paired full-length immunoglobulin light and heavy chain genes from hybridoma cell lines. When compared to Sanger sequencing of two hybridoma cell lines, long-read ONT sequencing was highly accurate, reliable, and amenable to high throughput. We further show that the method is applicable to single cells, allowing efficient antibody discovery in rare populations such as memory B cells. In summary, NAb-seq promises to accelerate identification and validation of hybridoma antibodies as well as antibodies from single B cells used in research, diagnostics and therapeutics.
- Published
- 2022
10. Effect of Chain-End Chemistries on the Efficiency of Coupling Antibodies to Polymers Using Unnatural Amino Acids
- Author
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Adrian V. Fuchs, S S Hema Preethi, Kristofer J. Thurecht, Christopher B. Howard, Amal J. Sivaram, Craig A. Bell, Andri Wardiana, and Nicholas L. Fletcher
- Subjects
chemistry.chemical_classification ,Polymers and Plastics ,Cycloaddition Reaction ,Chemistry ,Polymers ,Biomolecule ,Organic Chemistry ,Nanotechnology ,Chain transfer ,02 engineering and technology ,Raft ,Polymer ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,0104 chemical sciences ,Polymerization ,Materials Chemistry ,Click chemistry ,Click Chemistry ,Nanocarriers ,Amino Acids ,0210 nano-technology ,Conjugate - Abstract
Novel conjugates that incorporate strategies for increasing the therapeutic payload, such as targeted polymeric delivery vehicles, have great potential in overcoming limitations of conventional antibody therapies that often exhibit immunogenicity and limited drug loading. Click chemistry has significantly expanded the toolbox of effective strategies for developing hybrid polymer-biomolecule conjugates, however, effective systems require orthogonality between the polymer and biomolecule chemistries to achieve efficient coupling. Here, three cycloaddition-based strategies for antibody conjugation to polymeric carriers are explored and show that a purely radical-based method for polymer synthesis and subsequent biomolecule attachment has a trade-off between coupling efficiency of the antibody and the ability to synthesize polymers with controlled chemical properties. It is shown that careful consideration of both coupling chemistries as well as the potential effect of how this modulates the chemical properties of the polymer nanocarrier should be considered during the development of such systems. The strategies described offer insight into improving conjugate development for therapeutic and theranostic applications. In this system, polymerization using conventional and established reversible addition fragmentation chain transfer (RAFT) agents, followed by multiple post-modification steps, always leads to systems with more defined chemical architectures compared to strategies that utilize alkyne-functional RAFT agents.
- Published
- 2020
11. Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
- Author
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Lucía Fernández, Manoj Garg, H. Phillip Koeffler, Lee Yung Shih, Qiao-Yang Sun, Yan-Yi Jiang, Der Cherng Liang, Masashi Sanada, Yasunobu Nagata, Xin-Yi Loh, Wenwen Chien, Kar Tong Tan, De-Chen Lin, Hema Preethi, Hagop M. Kantarjian, Henry Yang, Li Zhen Liu, Ling-Wen Ding, Su Lin Lim, Steven M. Kornblau, Anand Mayakonda Thippeswamy, Jin Fen Xiao, Vikas Madan, Norihiko Kawamata, Seishi Ogawa, Liang Xu, Allen Eng Juh Yeoh, Michael Lill, and Satoru Miyano
- Subjects
0301 basic medicine ,Male ,Cancer Research ,ARID1A ,DNA Mutational Analysis ,Bioinformatics ,Receptor tyrosine kinase ,Mice ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Cancer ,Pediatric ,biology ,Blotting ,High-Throughput Nucleotide Sequencing ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Oncology ,Child, Preschool ,Female ,Tyrosine kinase ,Western ,Biotechnology ,Pediatric Research Initiative ,Adolescent ,Pediatric Cancer ,Childhood Leukemia ,Blotting, Western ,Oncology and Carcinogenesis ,Article ,03 medical and health sciences ,Rare Diseases ,Clinical Research ,medicine ,Genetics ,Animals ,Humans ,Epigenetics ,Oncology & Carcinogenesis ,Preschool ,Transcription factor ,Infant ,medicine.disease ,030104 developmental biology ,Good Health and Well Being ,CTCF ,Mutation ,biology.protein - Abstract
Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. Cancer Res; 77(2); 390–400. ©2016 AACR.
- Published
- 2017
12. Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
- Author
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Xin-Yi Loh, Manoj Garg, Hagop M. Kantarjian, Anand Mayakonda, Yasunobu Nagata, Wenwen Chien, Masashi Sanada, Seishi Ogawa, De-Chen Lin, Qiao-Yang Sun, Yan-Yi Jiang, Allen Eng Juh Yeoh, Vikas Madan, Norihiko Kawamata, Lucía Fernández, Liang Xu, Su Lin Lim, Kar Tong Tan, Michael Lill, Der-Cherng Liang, Lee-Yung Shih, Satoru Miyano, Xiao Jin-Fen, Li-Zhen Liu, S S Hema Preethi, Henry Yang, Steven M. Kornblau, Ling-Wen Ding, and H. Phillip Koeffler
- Subjects
0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Genetics ,Immunology ,EZH2 ,Cell Biology ,Hematology ,Histone acetyltransferase ,Biology ,medicine.disease_cause ,Biochemistry ,Chromatin remodeling ,03 medical and health sciences ,030104 developmental biology ,Cancer research ,medicine ,biology.protein ,Epigenetics ,KRAS ,EP300 ,Exome - Abstract
Pediatric ALL is the most common childhood tumor and the leading cause of childhood cancer deaths. To gain a better understanding of the landscape of somatic mutations in ALL, we performed whole exome and targeted sequencing of 240 pediatric B-ALL patients with their matched remission samples. The significantly mutated genes fall into several common categories: RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment and p53/cell cycle pathway. RAS/receptor tyrosine kinases: the most frequently mutated genes were members of RAS signaling (NRAS, KRAS, FLT3, PTPN11). Besides the well know hotspot mutations [G12D/V/C (NRAS 13 cases, KRAS 13 cases), G13D (NRAS 14 cases, KRAS 11 cases) and Q61H/L/R/K (NRAS 15 cases, KRAS 1 case)], novel mutational sites were also identified for KRAS: A146T/P (3 cases), K117N/T (4 cases) and V14I (1 case). High frequency missense mutations of PTPN11 clustered in SH2 domain (included the canonical hotspot A72T (5 cases) and E76K/V (4 cases)) and tyrosine-phosphatase catalytic domain (G503R/V). For FLT3, well-appreciated activating hotspot mutations in the kinase domain (D835Y/Y842C) and several novel recurrent mutationswere identified. Epigenetic regulators: hotspot mutations were identified in histone H3K36 methyltransferase WHSC1. Mutation E1099K located in the SET domain, was identified in 10 patients as well as two of the 5 ALL cell lines that we sequenced (RS4;11, SEM). Stable silencing of E1099K mutant WHSC1 in RS4;11 cells by either lentiviral shRNA or CRISPR guide RNA (sgRNA) markedly reduced clonogenic growth both in vitro and in vivo, underscoring the critical role of WHSC1 in lymphoid malignancies. Two highly-related histone/non-histone acetyltransferases, CREBBP and EP300, were also prominently mutated in our cohort. Mutations of CREBBP predominantly occurred in the acetyltransferase domain, particularly in the hotspot R1446C/H. Mutations of chromatin remodeling genes (ARID1A and ARID2) have been identified in a number of cases. Silencing of ARID1A in ALL cell lines by lentiviral shRNA resulted in upregulation of the pro-growth regulator c-MYC, while forced expression of ARID1A reduced c-MYC luciferase reporter activity. In addition, silencing of ARID1A by either shRNA or CRISPR-sgRNA resulted in enhanced clonogenic growth, suggesting that ARID1A may be involved in the c-MYC pathway and modulates the ALL cell proliferation. Mutations of epigenetic regulators were also found in the polycomb complex (EZH2, EED, SUZ12), chromatin/nucleosome structure modifying proteins (CHD2, CHD3, CHD4), TET family proteins [TET1 (2 cases), TET2 (5 cases)] and histone modification proteins (HDAC1, SIRT1, BCOR, BRD8, lysine demethylase PHF2/KDM6A, histone acetyltransferase KAT6B). Transcription factors and p53/cell cycle pathway: a number of alterations of transcription factors essential for hematopoietic and lymphoid differentiation were noted including the lineage regulator PAX5 (5 missense, 3 indels) and ETV6 (6 cases, 3 were frameshift indel and 1 was a splice-site mutations). In addition, mutations were also found in other lineage transcription factors (IKZF2, IKZF3, EBF1), WT1 (6 cases, including 3 indels and 1 stop-gain mutations), RUNX family member [RUNX2 (7 cases), RUNX1 (1 case)], ERG1 (3 cases), GATA1/3 (1 case each) and CTCF. Somatic mutations of genes involved in the p53 pathway occurred in 18 patients, including TP53, ATM and the kinases that regulate p53 activities (HIPK1, HIPK2). Germline TP53 pathogenic variants were found in these 2 patients. Taken together, we extensively interrogated the mutational landscape of a large cohort of pediatric ALL samples by exome and targeted resequencing. This study provides a detailed mutational portrait of pediatric ALL and gives new insights into the molecular pathogenesis of this disease. Disclosures Kantarjian: Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Ogawa:Sumitomo Dainippon Pharma: Research Funding; Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding.
- Published
- 2016
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