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43 results on '"Stonestrom, Aaron"'

3. MEN1 mutations mediate clinical resistance to menin inhibition

Author

Perner, Florian, Stein, Eytan M., Wenge, Daniela V., Singh, Sukrit, Kim, Jeonghyeon, Apazidis, Athina, Rahnamoun, Homa, Anand, Disha, Marinaccio, Christian, Hatton, Charlie, Wen, Yanhe, Stone, Richard M., Schaller, David, Mowla, Shoron, Xiao, Wenbin, Gamlen, Holly A., Stonestrom, Aaron J., Persaud, Sonali, Ener, Elizabeth, Cutler, Jevon A., Doench, John G., McGeehan, Gerard M., Volkamer, Andrea, Chodera, John D., Nowak, Radosław P., Fischer, Eric S., Levine, Ross L., Armstrong, Scott A., and Cai, Sheng F.

Published
2023
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4. Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia

Author

McCarter, Joseph G. W., Nemirovsky, David, Famulare, Christopher A., Farnoud, Noushin, Mohanty, Abhinita S., Stone-Molloy, Zoe S., Chervin, Jordan, Ball, Brian J., Epstein-Peterson, Zachary D., Arcila, Maria E., Stonestrom, Aaron J., Dunbar, Andrew, Cai, Sheng F., Glass, Jacob L., Geyer, Mark B., Rampal, Raajit K., Berman, Ellin, Abdel-Wahab, Omar I., Stein, Eytan M., Tallman, Martin S., Levine, Ross L., Goldberg, Aaron D., Papaemmanuil, Elli, Zhang, Yanming, Roshal, Mikhail, Derkach, Andriy, and Xiao, Wenbin

Published
2023
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5. High risk and silent clonal hematopoietic genotypes in patients with non-hematologic cancer

Author

Stonestrom, Aaron James, primary, Menghrajani, Kamal N, additional, Devlin, Sean M., additional, Franch-Expósito, Sebastià, additional, Ptashkin, Ryan N, additional, Patel, Swara Y, additional, Spitzer, Barbara, additional, Wu, Xiaodi, additional, Jee, Justin, additional, Sánchez Vela, Pablo, additional, Milbank, Jennifer, additional, Shah, Ronak H, additional, Mohanty, Abhinita S., additional, Brannon, Rose Rose, additional, Xiao, Wenbin, additional, Berger, Michael F., additional, Mantha, Simon, additional, and Levine, Ross L, additional

Published
2023
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7. Occupancy by key transcription factors is a more accurate predictor of enhancer activity than histone modifications or chromatin accessibility.

Author

Dogan, Nergiz, Wu, Weisheng, Morrissey, Christapher, Chen, Kuan-Bei, Stonestrom, Aaron, Long, Maria, Keller, Cheryl, Cheng, Yong, Jain, Deepti, Visel, Axel, Pennacchio, Len, Weiss, Mitchell, Blobel, Gerd, and Hardison, Ross

Subjects
Enhancer assay, Functional genomics, GATA1, Gene regulation, Histone modifications, TAL1
Abstract

BACKGROUND: Regulated gene expression controls organismal development, and variation in regulatory patterns has been implicated in complex traits. Thus accurate prediction of enhancers is important for further understanding of these processes. Genome-wide measurement of epigenetic features, such as histone modifications and occupancy by transcription factors, is improving enhancer predictions, but the contribution of these features to prediction accuracy is not known. Given the importance of the hematopoietic transcription factor TAL1 for erythroid gene activation, we predicted candidate enhancers based on genomic occupancy by TAL1 and measured their activity. Contributions of multiple features to enhancer prediction were evaluated based on the results of these and other studies. RESULTS: TAL1-bound DNA segments were active enhancers at a high rate both in transient transfections of cultured cells (39 of 79, or 56%) and transgenic mice (43 of 66, or 65%). The level of binding signal for TAL1 or GATA1 did not help distinguish TAL1-bound DNA segments as active versus inactive enhancers, nor did the density of regulation-related histone modifications. A meta-analysis of results from this and other studies (273 tested predicted enhancers) showed that the presence of TAL1, GATA1, EP300, SMAD1, H3K4 methylation, H3K27ac, and CAGE tags at DNase hypersensitive sites gave the most accurate predictors of enhancer activity, with a success rate over 80% and a median threefold increase in activity. Chromatin accessibility assays and the histone modifications H3K4me1 and H3K27ac were sensitive for finding enhancers, but they have high false positive rates unless transcription factor occupancy is also included. CONCLUSIONS: Occupancy by key transcription factors such as TAL1, GATA1, SMAD1, and EP300, along with evidence of transcription, improves the accuracy of enhancer predictions based on epigenetic features.

Published
2015

8. Targeting mutations in cancer

Author

Waarts, Michael R., Stonestrom, Aaron J., Park, Young C., and Levine, Ross I.

Subjects
Oncology, Experimental, Nucleotide sequencing -- Methods, Gene mutations -- Research, DNA sequencing -- Methods, Cancer -- Care and treatment -- Genetic aspects -- Research, Molecular targeted therapy -- Methods, Genetic screening -- Methods, Health care industry
Abstract

Targeted therapies have come to play an increasingly important role in cancer therapy over the past two decades. This success has been made possible in large part by technological advances in sequencing, which have greatly advanced our understanding of the mutational landscape of human cancer and the genetic drivers present in individual tumors. We are rapidly discovering a growing number of mutations that occur in targetable pathways, and thus tumor genetic testing has become an important component in the choice of appropriate therapies. Targeted therapy has dramatically transformed treatment outcomes and disease prognosis in some settings, whereas in other oncologic contexts, targeted approaches have yet to demonstrate considerable clinical efficacy. In this Review, we summarize the current knowledge of targetable mutations that occur in a range of cancers, including hematologic malignancies and solid tumors such as non-small cell lung cancer and breast cancer. We outline seminal examples of druggable mutations and targeting modalities and address the clinical and research challenges that must be overcome to maximize therapeutic benefit., Introduction Advances in the classical cancer treatment modalities of standard cytotoxic chemotherapy, radiotherapy, and surgery have led to reductions in cancer mortality rates over the last several decades; however, major [...]

Published
2022
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9. The hematopoietic saga of clonality in sickle cell disease

Author

Stonestrom, Aaron J. and Levine, Ross L.

Subjects
Sickle cell anemia -- Genetic aspects -- Development and progression -- Care and treatment, Medical research, Medicine, Experimental, Hematopoiesis -- Research, Leukemia -- Risk factors -- Development and progression, Cellular therapy -- Research, Hematopoietic stem cells -- Genetic aspects -- Health aspects, Health care industry
Abstract

Sickle cell disease (SCD) is associated with an increased risk of vascular-occlusive events and of leukemia. Clonal hematopoiesis (CH) may increase both risks. In turn, physiologic abnormalities in SCD may modify the incidence and/or distribution of genetic alterations in CH. In a recent issue of the JCI, Liggett et al. found no difference in CH rate between individuals with versus without SCD. Here we contextualize this report and discuss the complex interplay between CH and SCD with particular attention to consequences for emerging gene therapies. We further consider the limitations in our current understanding of these topics that must be addressed in order to optimize therapeutic strategies for SCD., Sickle cell disease presents specific challenges for hematopoiesis Sickle cell disease (SCD) is a monogenic blood disorder that affects millions of people worldwide. SCD is commonly caused by homozygosity for [...]

Published
2022
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12. Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia: an appraisal of the new WHO and IC classifications and ELN risk stratification

Author

McCarter, Joseph GW., primary, Nemirovsky, David, additional, Famulare, Christopher A., additional, Farnoud, Noushin, additional, Mohanty, Abhinita S., additional, Stone-Molloy, Zoe S., additional, Chervin, Jordan, additional, Ball, Brian J., additional, Epstein-Peterson, Zachary D., additional, Arcila, Maria E., additional, Stonestrom, Aaron J., additional, Dunbar, Andrew, additional, Cai, Sheng F., additional, Glass, Jacob L., additional, Geyer, Mark B., additional, Rampal, Raajit K., additional, Berman, Ellin, additional, Abdel-Wahab, Omar I., additional, Stein, Eytan M., additional, Tallman, Martin S., additional, Levine, Ross L., additional, Goldberg, Aaron D., additional, Papaemmanuil, Elli, additional, Zhang, Yanming, additional, Roshal, Mikhail, additional, Derkach, Andriy, additional, and Xiao, Wenbin, additional

Published
2022
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14. MEN1mutations mediate clinical resistance to menin inhibition

Author

Perner, Florian, Stein, Eytan M., Wenge, Daniela V., Singh, Sukrit, Kim, Jeonghyeon, Apazidis, Athina, Rahnamoun, Homa, Anand, Disha, Marinaccio, Christian, Hatton, Charlie, Wen, Yanhe, Stone, Richard M., Schaller, David, Mowla, Shoron, Xiao, Wenbin, Gamlen, Holly A., Stonestrom, Aaron J., Persaud, Sonali, Ener, Elizabeth, Cutler, Jevon A., Doench, John G., McGeehan, Gerard M., Volkamer, Andrea, Chodera, John D., Nowak, Radosław P., Fischer, Eric S., Levine, Ross L., Armstrong, Scott A., and Cai, Sheng F.

Abstract

Chromatin-binding proteins are critical regulators of cell state in haematopoiesis1,2. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1gene, to sustain aberrant leukaemogenic gene expression programs3–5. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin–MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1(ref. 6). Here we identified somatic mutations in MEN1at the revumenib–menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor–menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug–target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.

Published
2023
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17. Chemotherapy and COVID-19 Outcomes in Patients With Cancer

Author

Jee, Justin, primary, Foote, Michael B., additional, Lumish, Melissa, additional, Stonestrom, Aaron J., additional, Wills, Beatriz, additional, Narendra, Varun, additional, Avutu, Viswatej, additional, Murciano-Goroff, Yonina R., additional, Chan, Jason E., additional, Derkach, Andriy, additional, Philip, John, additional, Belenkaya, Rimma, additional, Kerpelev, Marina, additional, Maloy, Molly, additional, Watson, Adam, additional, Fong, Chris, additional, Janjigian, Yelena, additional, Diaz, Luis A., additional, Bolton, Kelly L., additional, and Pessin, Melissa S., additional

Published
2020
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18. Biochemical characterization of phosphoryl transfer involving HPr of the phosphoenolpyruvate-dependent phosphotransferase system in Treponema denticola, an organism that lacks PTS permeases

Author

Gonzalez, Claudio F., Stonestrom, Aaron J., Lorca, Graciela L., and Saier, Milton H., Jr.

Subjects
Proteins -- Chemical properties, Treponema pallidum -- Chemical properties, Phosphotransferases -- Research, Biological sciences, Chemistry
Abstract

Treponema pallidum and Treponema denticola encode within their genomes homologues of energy coupling and regulatory proteins of the phosphoenolpyruvate: sugar phosphotransferase system (PTS) but no recognizable homologues of PTS permeases. The first biochemical description of PTS phosphoryl-transfer chains in an organism that lacks PTS permeases is described.

Published
2005

19. Oncologic Immunomodulatory Agents in Patients with Cancer and COVID-19

Author

Jee, Justin, primary, Stonestrom, Aaron J., additional, Devlin, Sean, additional, Nguyentran, Teresa, additional, Wills, Beatriz, additional, Narendra, Varun, additional, Foote, Michael B., additional, Lumish, Melissa, additional, Vardhana, Santosha, additional, Pastores, Stephen M., additional, Korde, Neha, additional, Patel, Dhwani, additional, Horwitz, Steven, additional, Scordo, Michael, additional, and Daniyan, Anthony, additional

Published
2020
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23. Interrogating Histone Acetylation and BRD4 as Mitotic Bookmarks of Transcription

Author

Behera, Vivek, primary, Stonestrom, Aaron J., additional, Hamagami, Nicole, additional, Hsiung, Chris C., additional, Keller, Cheryl A., additional, Giardine, Belinda, additional, Sidoli, Simone, additional, Yuan, Zuo-Fei, additional, Bhanu, Natarajan V., additional, Werner, Michael T., additional, Wang, Hongxin, additional, Garcia, Benjamin A., additional, Hardison, Ross C., additional, and Blobel, Gerd A., additional

Published
2019
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24. High risk and silent clonal hematopoietic genotypes in patients with non-hematologic cancer

Author

Stonestrom, Aaron J., Menghrajani, Kamal N., Devlin, Sean M., Franch-Expósito, Sebastià, Ptashkin, Ryan N., Patel, Swara Y., Spitzer, Barbara, Wu, Xiaodi, Jee, Justin, Sánchez-Vela, Pablo, Milbank, Jennifer H., Shah, Ronak H., Mohanty, Abhinita S., Brannon, A. Rose, Xiao, Wenbin, Berger, Michael F., Mantha, Simon, and Levine, Ross L.

Abstract

1.High risk CH mutations in JAK2, RUNX1, and XPO1 anticipatehematologic malignancy in cancer patients2.Functionally neutral silent CH variants are significant predictors of hematologic malignancy risk

Published
2024
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26. The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries

Author

Hsu, Sarah C., primary, Gilgenast, Thomas G., additional, Bartman, Caroline R., additional, Edwards, Christopher R., additional, Stonestrom, Aaron J., additional, Huang, Peng, additional, Emerson, Daniel J., additional, Evans, Perry, additional, Werner, Michael T., additional, Keller, Cheryl A., additional, Giardine, Belinda, additional, Hardison, Ross C., additional, Raj, Arjun, additional, Phillips-Cremins, Jennifer E., additional, and Blobel, Gerd A., additional

Published
2017
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27. The BET Protein BRD2 Cooperates with CTCF to Enforce a Transcriptional Boundary in Erythroid Cells

Author

Hsu, Sarah C., primary, Bartman, Caroline, additional, Stonestrom, Aaron J, additional, Edwards, Christopher R, additional, Gilgenast, Thomas, additional, Emerson, Daniel, additional, Huang, Peng, additional, Werner, Michael T., additional, Jahn, Kristen, additional, Keller, Cheryl A., additional, Giardine, Belinda, additional, Hardison, Ross C., additional, Raj, Arjun, additional, Phillips-Cremins, Jennifer E., additional, and Blobel, Gerd A., additional

Published
2016
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28. A hyperactive transcriptional state marks genome reactivation at the mitosis–G1 transition

Author

Hsiung, Chris C.-S., primary, Bartman, Caroline R., additional, Huang, Peng, additional, Ginart, Paul, additional, Stonestrom, Aaron J., additional, Keller, Cheryl A., additional, Face, Carolyne, additional, Jahn, Kristen S., additional, Evans, Perry, additional, Sankaranarayanan, Laavanya, additional, Giardine, Belinda, additional, Hardison, Ross C., additional, Raj, Arjun, additional, and Blobel, Gerd A., additional

Published
2016
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32. Occupancy by key transcription factors is a more accurate predictor of enhancer activity than histone modifications or chromatin accessibility

Author

Dogan, Nergiz, primary, Wu, Weisheng, additional, Morrissey, Christapher S, additional, Chen, Kuan-Bei, additional, Stonestrom, Aaron, additional, Long, Maria, additional, Keller, Cheryl A, additional, Cheng, Yong, additional, Jain, Deepti, additional, Visel, Axel, additional, Pennacchio, Len A, additional, Weiss, Mitchell J, additional, Blobel, Gerd A, additional, and Hardison, Ross C, additional

Published
2015
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35. Molecular Basis and Consequences of the Cytochrome c-tRNA Interaction.

Author

Cuiping Liu, Stonestrom, Aaron J., Christian, Thomas, Jeongsik Yong, Ryuichi Takase, Ya-Ming Hou, and Xiaolu Yang

Subjects
*CYTOCHROME c, *TRANSFER RNA, *MOLECULAR genetics, *APOPTOSIS, *CYTOSOL, *PROTEOLYTIC enzymes
Abstract

The intrinsic apoptosis pathway occurs through the release of mitochondrial cytochrome c to the cytosol, where it promotes activation of the caspase family of proteases. The observation that tRNA binds to cytochrome c revealed a previously unexpected mode of apoptotic regulation. However, the molecular characteristics of this interaction, and its impact on each interaction partner, are not well understood. Using a novel fluorescence assay, we show here that cytochrome c binds to tRNA with an affinity comparable with other tRNA-protein binding interactions and with a molecular ratio of ~3:1. Cytochrome c recognizes the tertiary structural features of tRNA, particularly in the core region. This binding is independent of the charging state of tRNA but is regulated by the redox state of cytochrome c. Compared with reduced cytochrome c, oxidized cytochrome c binds to tRNA with a weaker affinity, which correlates with its stronger pro-apoptotic activity. tRNA binding both facilitates cytochrome c reduction and inhibits the peroxidase activity of cytochrome c, which is involved in its release from mitochondria. Together, these findings provide new insights into the cytochrome c-tRNA interaction and apoptotic regulation. [ABSTRACT FROM AUTHOR]

Published
2016
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38. DOT1L/KMT4 Recruitment and H3K79 Methylation Are Ubiquitously Coupled with Gene Transcription in Mammalian Cells

Author

Steger, David J., primary, Lefterova, Martina I., additional, Ying, Lei, additional, Stonestrom, Aaron J., additional, Schupp, Michael, additional, Zhuo, David, additional, Vakoc, Adam L., additional, Kim, Ja-Eun, additional, Chen, Junjie, additional, Lazar, Mitchell A., additional, Blobel, Gerd A., additional, and Vakoc, Christopher R., additional

Published
2008
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41. tRNA and cytochrome c in cell death and beyond

Author

Mei, Yide, Yong, Jeongsik, Stonestrom, Aaron, and Yang, Xiaolu

Abstract

Both transfer RNA (tRNA) and cytochrome care essential to cellular function: tRNA mediates protein synthesis while cytochrome cis required for oxidative phosphorylation and apoptosis induction. tRNA has recently been implicated as a direct regulator of the well-conserved apoptotic role of cytochrome c. This finding questions how these molecules interact to coordinate biosynthesis, energy production and apoptosis at an exciting forefront of research. Here we review the diversity and dynamics of tRNA and how this class of non-coding RNAs may regulate the role of cytochrome cin apoptosis. We comment on unanswered questions in the cell biology of this interaction and how answers may influence our understanding of disease.

Published
2010
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43. Quantification of Plasma Proteins from Idiopathic Multicentric Castleman Disease Flares and Remissions Reveals ‘Chemokine Storm’ and Separates Clinical Subtypes

Author

Pierson, Sheila K, Stonestrom, Aaron James, Ruth, Jason R, Shilling, Dustin, Li, Hongzhe, Ren, Yue, Stone, Katie, van Rhee, Frits, and Fajgenbaum, David C

Abstract

Introduction: Human Herpesvirus-8(HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a poorly understood disease involving polyclonal lymphoproliferation, constitutional symptoms, and life-threatening multi-organ failure. Some patients experience thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO Syndrome) while others (non-TAFRO) experience thrombocytosis and hypergammaglobulinemia. Though the etiology is unknown, iMCD symptoms and disease progression are believed to be driven by a cytokine storm, often including interleukin-6 (IL-6). Anti-IL-6 therapy with siltuximab was approved by the FDA to treat iMCD based on superior efficacy compared to placebo in a randomized trial. However, approximately one-half of iMCD patients do not respond to anti-IL-6 therapy. Few rational treatment options exist for anti-IL-6 non-responders, because alternative driver cytokines and signaling pathways are not known. Furthermore, no positive diagnostic biomarkers exist for iMCD. We systematically characterized proteomic changes that occur in iMCD patients between flare and remission to identify key cytokines, signaling pathways, and cell types that may be involved in pathogenesis.

Published
2017
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