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15 results on '"Shukla, Sachet A"'

1. Enriched Signalling Pathways in Venetoclax-Relapsed Chronic Lymphocytic Leukemia (CLL) Cells and Targeting Using a Protac-Based Bcl-2/Bcl-Xl Degrader

Author

Diaz Rohena, Daisy, primary, Peris Cuesta, Arnau, additional, Slawin, Bailey, additional, Ravikrishnan, Janani, additional, Liu, Chaomei, additional, Williams, Charmelle, additional, Hu, Wanyi, additional, Zhang, Peiyi, additional, Thompson, Philip, additional, Wierda, William G., additional, Jain, Nitin, additional, Shukla, Sachet, additional, Zheng, Guangrong, additional, Zhou, Daohong, additional, Woyach, Jennifer A., additional, and Sampath, Deepa, additional

Published
2023
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2. A cloning and expression system to probe T-cell receptor specificity and assess functional avidity to neoantigens

Author

Hu, Zhuting, Anandappa, Annabelle J., Sun, Jing, Kim, Jintaek, Leet, Donna E., Bozym, David J., Chen, Christina, Williams, Louise, Shukla, Sachet A., Zhang, Wandi, Tabbaa, Diana, Steelman, Scott, Olive, Oriol, Livak, Kenneth J., Kishi, Hiroyuki, Muraguchi, Atsushi, Guleria, Indira, Stevens, Jonathan, Lane, William J., Burkhardt, Ute E., Fritsch, Edward F., Neuberg, Donna, Ott, Patrick A., Keskin, Derin B., Hacohen, Nir, and Wu, Catherine J.

Published
2018
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3. Distinct Evolutionary Patterns in Chronic Lymphocytic Leukemia (CLL) during Resistance to Graft-Versus-Leukemia (GvL)

Author

Bachireddy, Pavan, primary, Ennis, Christina, primary, Nguyen, Vinhkhang N, primary, Barkas, Nikolas, primary, Shukla, Sachet, primary, Clement, Kendell, primary, Freeman, Samuel, primary, Gohil, Satyen H, primary, Bavli, Natalie, primary, Elagina, Liudmila, primary, Leshchiner, Ignaty, primary, Brown, Jennifer R., primary, Getz, Gad, primary, Ho, Vincent T., primary, Neuberg, Donna S, primary, Soiffer, Robert J., primary, Ritz, Jerome, primary, Alyea, Edwin P., primary, Kharchenko, Peter, primary, and Wu, Catherine J., primary

Published
2019
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4. Clonal and Single Cell Dynamics of Resistance to Graft-Versus-Leukemia (GvL) in Chronic Lymphocytic Leukemia (CLL)

Author

Bachireddy, Pavan, primary, Barkas, Nikolaos, additional, Shukla, Sachet A, additional, Freeman, Samuel, additional, Elagina, Liudmila, additional, Nguyen, Vinhkhang N, additional, Clement, Kendell, additional, Leshchiner, Ignaty, additional, Brown, Jennifer R., additional, Neuberg, Donna S, additional, Ho, Vincent T., additional, Soiffer, Robert J., additional, Ritz, Jerome, additional, Getz, Gad, additional, Alyea, Edwin P., additional, Kharchenko, Peter, additional, and Wu, Catherine J., additional

Published
2018
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6. ASXL1 Truncating Mutations Drive Leukemic Resistance to T Cell Attack

Author

McCurry, Dustin, Ge, Zhongqi, Lee, Jaehyun, Raparla, Pranaya, Koehnke, Thomas, Pasumarthi, Rishi, Leng, Xiaohong, Pasvolsky, Oren, Nguyen, Vinhkhang, Maurer, Katie, Li, Shuqiang, Livak, Kenneth J., Azizi, Elham, Soiffer, Robert J., Shukla, Sachet, Majeti, Ravindra, Ritz, Jerome, Wu, Catherine J, Molldrem, Jeffrey J., and Bachireddy, Pavan

Abstract

Restoration of graft-versus leukemia activity underlies the efficacy of donor lymphocyte infusion (DLI), a curative immunotherapy for leukemic relapse following allogeneic stem cell transplant (SCT). We found that while specific exhausted T cell subsets defined DLI response, no pattern of T cell dysfunction appeared in nonresponders (NRs) [PMID: 34758319]. We hypothesized that leukemic molecular pathways define DLI resistance (DLIr).

Published
2023
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7. High-Throughput Identification of Graft-Vs-Leukemia TCRs in AML Patient Samples after Allogeneic Stem Cell Transplantation

Author

Tubo, Noah J, Wang, Duncheng, He, Qiuming, Chen, Yibin, Ngai, Ho, Huang, Yanqing, Kerros, Celine, Mao, Xizeng, Liang, Shoudan, Shukla, Sachet, Peris Cuesta, Arnau, Bachireddy, Pavan, Alcantara Montiel, Julio, Alatrash, Gheath, Koppikar, Priya, and Molldrem, Jeffrey J.

Abstract

For patients with intermediate and high-risk AML/MDS, allogeneic stem cell transplantation (aSCT) is a potentially curative therapy. Efficacy is driven by the graft-versus-leukemia (GvL) response, in which donor-derived T cells recognize peptide:MHC antigens presented by leukemia cells, and subsequently kill them. The antigens that drive GvL responses are attractive therapeutic targets for engineered cell therapies and/or biologics. However, only a small number of GvL antigens have been identified, limiting the therapeutic potential of targeted immunotherapies. Deep interrogation of the T cell repertoires of patients who have responded favorably to aSCT presents an opportunity to identify bona fideGvL antigens, but high-throughput methods need to be developed to do this effectively.

Published
2023
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9. Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL

Author

Wang, Lili, primary, Shalek, Alex K., additional, Lawrence, Mike, additional, Ding, Ruihua, additional, Gaublomme, Jellert T., additional, Pochet, Nathalie, additional, Stojanov, Petar, additional, Sougnez, Carrie, additional, Shukla, Sachet A., additional, Stevenson, Kristen E., additional, Zhang, Wandi, additional, Wong, Jessica, additional, Sievers, Quinlan L., additional, MacDonald, Bryan T., additional, Vartanov, Alexander R., additional, Goldstein, Natalie R., additional, Neuberg, Donna, additional, He, Xi, additional, Lander, Eric, additional, Hacohen, Nir, additional, Regev, Aviv, additional, Getz, Gad, additional, Brown, Jennifer R., additional, Park, Hongkun, additional, and Wu, Catherine J., additional

Published
2014
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10. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia

Author

Rajasagi, Mohini, primary, Shukla, Sachet A., additional, Fritsch, Edward F., additional, Keskin, Derin B., additional, DeLuca, David, additional, Carmona, Ellese, additional, Zhang, Wandi, additional, Sougnez, Carrie, additional, Cibulskis, Kristian, additional, Sidney, John, additional, Stevenson, Kristen, additional, Ritz, Jerome, additional, Neuberg, Donna, additional, Brusic, Vladimir, additional, Gabriel, Stacey, additional, Lander, Eric S., additional, Getz, Gad, additional, Hacohen, Nir, additional, and Wu, Catherine J., additional

Published
2014
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12. Systematic Identification of Personal Mutated Tumor-Specific Neoantigens in CLL

Author

Rajasagi, Mohini, primary, Keskin, Derin, additional, Kim, Jintaek, additional, Zhang, Wandi, additional, Shukla, Sachet, additional, DeLuca, David, additional, Sidney, John, additional, Brusic, Vladimir, additional, Neuberg, Donna S., additional, Getz, Gad, additional, Lander, Eric S., additional, Hacohen, Nir, additional, and Wu, Catherine J., additional

Published
2012
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13. The Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

Author

Carrie Sougnez, Kristen E. Stevenson, Shukla Sachet, Wandi Zhang, Catherine J. Wu, Matthew Meyerson, Andrey Sivachenko, Dan-Avi Landau, Stacey Gabriel, Jennifer R. Brown, Scott L. Carter, Bethany Tesar, Donna Neuberg, Eric S. Lander, Michael S. Lawrence, Lili Wang, Gad Getz, Aaron McKenna, Alexander R. Vartanov, Petar Stojanov, Stacey M. Fernandes, and Kristian Cibulskis

Subjects
Genetics, Mutation, Chronic lymphocytic leukemia, Point mutation, Immunology, Cell Biology, Hematology, Biology, medicine.disease, medicine.disease_cause, Biochemistry, Somatic evolution in cancer, Leukemia, medicine, SNP, Sample collection, Exome sequencing
Abstract

Abstract 5 The impact of clonal heterogeneity on cancer progression in chronic lymphocytic leukemia (CLL) is not well understood. We hypothesized that the evolutionary dynamics of subclonal mutations contribute to the variations in disease tempo and response to therapy that characterize CLL. We therefore carried out a large-scale analysis of subclonal and clonal point mutations and copy-number alterations in 149 CLLs, detected by whole exome sequencing (WES) and SNP arrays. We utilized a novel computational approach, which integrates purity and local ploidy information, to infer the cancer cell fraction (CCF) of each mutation from WES data, and to classify mutations as clonal or subclonal. Subclonal mutations were detected in 146/149 CLLs and were enriched with putative cancer driver events (P=0.001). Furthermore, higher numbers of subclonal mutations were associated with prior anti-leukemia therapy (P=0.017). Together, these results suggest that a strong extrinsic selection pressure, such as cytotoxic treatment, promotes the expansion of fitter subclones, driving them to above our detection threshold (CCF of ∼0.10). The order of mutation acquisition may be inferred from the aggregate frequencies at which driver events are clonal or subclonal, as clonal mutations represent earlier events and subclonal later events. Of the 149 samples, we found 3 drivers (MYD88, trisomy 12, and del(13q)) that were clonal in 80–100% of samples harboring these alterations –significantly higher than other driver events (q We directly assessed the evolution of somatic mutations in 18 patients, in which data from two distant timepoints were available. Clonal evolution was observed in 11 of 18 patients (10 of 12 who received intervening treatment, but only 1 of 6 without intervening treatment, P=0.012) and confirmed that subclonal mutations (e.g., del(11q), SF3B1 and TP53) shifted towards clonality over time. Indeed, expanding subclonal mutations were enriched in putative drivers (P=0.021), suggesting that these mutations not only mark genetic evolution but also provide the fitness advantage driving it. Changes in the genetic composition of CLL cells with clonal evolution were associated with network level changes in gene expression. If treatment-associated genetic evolution leads to expansion of a fitter subclone, we would predict a shorter time to relapse in these individuals. Indeed, presence of a detectable subclonal driver mutation was associated with a shorter time to retreatment in these 18 samples (P=0.04), indicating that the presence of subclonal drivers adversely impacts clinical outcome. In the analysis of the full cohort of 149 samples, we observed that CLLs with subclonal driver mutations were associated with shorter times from diagnosis to first therapy (P=0.001) and between sample collection to treatment (P In conclusion, the analysis of clonal heterogeneity in CLL provides a glimpse into the past, present and future of a patient's disease. Through the cross-sectional analysis of 149 samples, we derived the number and genetic composition of clonal and subclonal mutations and thus uncovered footprints of the past history of CLL. Furthermore, we inferred a temporal order of genetic events implicated in CLL. Finally, our combined longitudinal and cross-sectional analyses revealed that knowledge of subclonal mutations anticipates the genetic composition of the future relapsing leukemia as well as the rapidity with which it will occur. These data challenge us to therapeutically address not only genetic targets but also their dynamic evolutionary landscape. Disclosures: No relevant conflicts of interest to declare.

Published
2012

14. A cloning and expression system to probe T-cell receptor specificity and assess functional avidity to neoantigens.

Author

Zhuting Hu, Anandappa, Annabelle J., Jing Sun, Jintaek Kim, Leet, Donna E., Bozym, David J., Chen, Christina, Williams, Louise, Shukla, Sachet A., Wandi Zhang, Tabbaa, Diana, Steelman, Scott, Olive, Oriol, Livak, Kenneth J., Hiroyuki Kishi, Atsushi Muraguchi, Guleria, Indira, Stevens, Jonathan, Lane, William J., and Burkhardt, Ute E.

Subjects
*T-cell receptor genes, *CHRONIC lymphocytic leukemia, *LEUKEMIA, *MELANOMA, *IMMUNOTHERAPY
Abstract

Recent studies have highlighted the promise of targeting tumor neoantigens to generate potent antitumor immune responses and provide strong motivation for improving our understanding of antigen-T-cell receptor (TCR) interactions. Advances in single-cell sequencing technologies have opened the door for detailed investigation of the TCR repertoire, providing paired information from TCRa and TCRb, which together determine specificity. However, a need remains for efficient methods to assess the specificity of discovered TCRs. We developed a streamlined approach for matching TCR sequences with cognate antigen through on-demand cloning and expression of TCRs and screening against candidate antigens. Here, we first demonstrate the system's capacity to identify viralantigen- specific TCRs and compare the functional avidity of TCRs specific for a given antigen target. We then apply this system to identify neoantigen-specific TCR sequences from patients with melanoma treated with personalized neoantigen vaccines and characterize functional avidity of neoantigen-specific TCRs. Furthermore, we use a neoantigenprediction pipeline to show that an insertion-deletion mutation in a putative chronic lymphocytic leukemia (CLL) driver gives rise to an immunogenic neoantigen mut-MGA, and use this approach to identify the mut-MGA-specific TCR sequence. This approach provides a means to identify and express TCRs, and then rapidly assess antigen specificity and functional avidity of a reconstructed TCR, which can be applied for monitoring antigenspecific T-cell responses, and potentially for guiding the design of effective T-cell-based immunotherapies. [ABSTRACT FROM AUTHOR]

Published
2018
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15. Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL.

Author

Lili Wang, Shalek, Alex K., Lawrence, Mike, Ding, Ruihua, Gaublomme, Jellert T., Pochet, Nathalie, Stojanov, Petar, Sougnez, Carrie, Shukla, Sachet A., Stevenson, Kristen E., Zhang, Wandi, Wong, Jessica, Sievers, Quinlan L., MacDonald, Bryan T., Vartanov, Alexander R., Goldstein, Natalie R., Neuberg, Donna, Xi He, Lander, Eric, and Hacohen, Nir

Subjects
*CANCER genetics, *SOMATIC mutation, *CARCINOGENESIS, *NUCLEOTIDE sequencing, *CHRONIC lymphocytic leukemia, *SILICON nanowires
Abstract

One major goal of cancer genome sequencing is to identify key genes and pathways that drive tumor pathogenesis. Although many studies have identified candidate driver genes based on recurrence of mutations in individual genes, subsets of genes with nonrecurrent mutations may also be defined as putative drivers if they affect a single biological pathway. In this fashion, we previously identified Wnt signaling as significantly mutated through large-scale massively parallel DNA sequencing of chronic lymphocytic leukemia (CLL). Here, we use a novel method of biomolecule delivery, vertical silicon nanowires, to efficiently introduce small interfering RNAs into CLL cells, and interrogate the effects of 8 of 15 mutated Wnt pathway members identified across 91 CLLs. In HEK293T cells, mutations in 2 genes did not generate functional changes, 3 led to dysregulated pathway activation, and 3 led to further activation or loss of repression of pathway activation. Silencing 4 of 8 mutated genes in CLL samples harboring the mutated alleles resulted in reduced viability compared with leukemia samples with wild-type alleles. We demonstrate that somatic mutations in CLL can generate dependence on this pathway for survival. These findings support the notion that nonrecurrent mutations at different nodes of the Wnt pathway can contribute to leukemogenesis. [ABSTRACT FROM AUTHOR]

Published
2014
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