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2. Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias

Author

Olson, Thomas L., Cheon, HeeJin, Xing, Jeffrey C., Olson, Kristine C., Paila, Umadevi, Hamele, Cait E., Neelamraju, Yaseswini, Shemo, Bryna C., Schmachtenberg, Matt, Sundararaman, Shriram K., Toro, Mariella F., Keller, Cheryl A., Farber, Emily A., Onengut-Gumuscu, Suna, Garrett-Bakelman, Francine E., Hardison, Ross C., Feith, David J., Ratan, Aakrosh, and Loughran, Thomas P., Jr

Published
2021
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10. Dissecting neural differentiation regulatory networks through epigenetic footprinting

Author

Ziller, Michael J., Edri, Reuven, Yaffe, Yakey, Donaghey, Julie, Pop, Ramona, Mallard, William, Issner, Robbyn, Gifford, Casey A., Goren, Alon, Xing, Jeffrey, Gu, Hongcang, Cacchiarelli, Davide, Tsankov, Alexander M., Epstein, Charles, Rinn, John L., Mikkelsen, Tarjei S., Kohlbacher, Oliver, Gnirke, Andreas, Bernstein, Bradley E., Elkabetz, Yechiel, and Meissner, Alexander

Subjects
Research, Genetic aspects, Epigenetic inheritance -- Research, Neural circuitry -- Research, Genetic research, Cell differentiation -- Research, Neurological research, Stem cells -- Genetic aspects
Abstract

We used the human embryonic stem (ES) cell line WA9 (also known as H9) expressing GFP under the HES5 promoter (4) to isolate defined neural progenitor populations of neuroepithelial (NE), [...], Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system (1-3). Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line (4). Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.

Published
2015

17. A Large Nonmetastatic Anaplastic Thyroid Cancer with Complete Thyroidal Confinement

Author

Xing, Jeffrey C., Bishop, Justin A., Mathioudakis, Nestoras, Agrawal, Nishant, and Tufano, Ralph P.

Subjects
Article Subject
Abstract

Anaplastic thyroid cancer (ATC) is rare but extremely aggressive, which accounts for about 2% of all thyroid cancers yet nearly 50% of thyroid-cancer-associated deaths in the United States. The median survival time from diagnosis is 5 months, with a 1-year survival rate of only 20%. We report here a case of ATC in a 56-year-old man who survived a large ATC. Preoperative fine-needle aspiration biopsy study to a large right thyroid mass suggested ATC. Total thyroidectomy with radical lateral neck and central neck dissection removed a well-circumscribed 9.5 cm tumor without extrathyroidal extension or lymphovascular invasion. All 73 lymph nodes removed were negative for metastasis. The tumor consisted of highly pleomorphic, undifferentiated cells with large zones of necrosis and loss of thyroid transcription factor-1 and thyroglobulin expression. A focal well-differentiated component and PAX8 expression confirmed its thyroid follicular cell origin. Nine months after postsurgical adjuvant concurrent radiation therapy and chemotherapy, the patient remained well without clinical, biochemical, and radiographical evidence for cancer recurrence. This is an unusual case of ATC in that it is one of the largest ATC tumors reported to display mild pathologic behavior and relatively long-term patient survival.

Published
2011
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18. Abstract B40: Synergistic cytotoxicity of ibrutinib and the BCL2 antagonist ABT-199 in mantle cell lymphoma and chronic lymphocytic leukemia: Molecular analysis reveals mechanisms of target interactions.

Author

Portell, Craig A., primary, Axelrod, Mark J., additional, Brett, Laura Kyle, additional, Gordon, Vicki L., additional, Capaldo, Brian, additional, Xing, Jeffrey, additional, Bekiranov, Stefan, additional, Williams, Michael E., additional, and Weber, Michael J., additional

Published
2015
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19. The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome

Author

Whitaker College of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Engreitz, Jesse Michael, Lander, Eric S., Pandya-Jones, Amy, McDonel, Patrick, Shishkin, Alexander, Sirokman, Klara, Surka, Christine, Kadri, Sabah, Xing, Jeffrey, Goren, Alon, Plath, Kathrin, Guttman, Mitchell, Lander, Eric Steven, Whitaker College of Health Sciences and Technology, Massachusetts Institute of Technology. Department of Biology, Engreitz, Jesse Michael, Lander, Eric S., Pandya-Jones, Amy, McDonel, Patrick, Shishkin, Alexander, Sirokman, Klara, Surka, Christine, Kadri, Sabah, Xing, Jeffrey, Goren, Alon, Plath, Kathrin, Guttman, Mitchell, and Lander, Eric Steven

Abstract

Many large noncoding RNAs (lncRNAs) regulate chromatin, but the mechanisms by which they localize to genomic targets remain unexplored. We investigated the localization mechanisms of the Xist lncRNA during X-chromosome inactivation (XCI), a paradigm of lncRNA-mediated chromatin regulation. During the maintenance of XCI, Xist binds broadly across the X chromosome. During initiation of XCI, Xist initially transfers to distal regions across the X chromosome that are not defined by specific sequences. Instead, Xist identifies these regions by exploiting the three-dimensional conformation of the X chromosome. Xist requires its silencing domain to spread across actively transcribed regions and thereby access the entire chromosome. These findings suggest a model in which Xist coats the X chromosome by searching in three dimensions, modifying chromosome structure, and spreading to newly accessible locations., Hertz Foundation, American Society for Engineering Education. National Defense Science and Engineering Graduate Fellowship, Broad Institute of MIT and Harvard

Published
2014

20. Dissecting neural differentiation regulatory networks through epigenetic footprinting

Author

Ziller, Michael J., primary, Edri, Reuven, additional, Yaffe, Yakey, additional, Donaghey, Julie, additional, Pop, Ramona, additional, Mallard, William, additional, Issner, Robbyn, additional, Gifford, Casey A., additional, Goren, Alon, additional, Xing, Jeffrey, additional, Gu, Hongcang, additional, Cacchiarelli, Davide, additional, Tsankov, Alexander M., additional, Epstein, Charles, additional, Rinn, John L., additional, Mikkelsen, Tarjei S., additional, Kohlbacher, Oliver, additional, Gnirke, Andreas, additional, Bernstein, Bradley E., additional, Elkabetz, Yechiel, additional, and Meissner, Alexander, additional

Published
2014
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21. Synergistic Cytotoxicity of Ibrutinib and the BCL2 Antagonist, ABT-199(GDC-0199) in Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL): Molecular Analysis Reveals Mechanisms of Target Interactions

Author

Portell, Craig A., primary, Axelrod, Mark, additional, Brett, L. Kyle, additional, Gordon, Vicki L, additional, Capaldo, Brian, additional, Xing, Jeffrey C, additional, Bekiranov, Stephan, additional, Williams, Michael E., additional, and Weber, Michael J., additional

Published
2014
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22. The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome

Author

Engreitz, Jesse M., primary, Pandya-Jones, Amy, additional, McDonel, Patrick, additional, Shishkin, Alexander, additional, Sirokman, Klara, additional, Surka, Christine, additional, Kadri, Sabah, additional, Xing, Jeffrey, additional, Goren, Alon, additional, Lander, Eric S., additional, Plath, Kathrin, additional, and Guttman, Mitchell, additional

Published
2013
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24. Genomic Landscape of TCR Alpha-Beta and TCR Gamma-Delta T-Large Granular Lymphocyte Leukemia

Author

Cheon, HeeJin, Xing, Jeffrey C., Moosic, Katharine B., Ung, Johnson, Chan, Vivian W., Chung, David S., Toro, Mariella F., Elghawy, Omar, Wang, John S., Hamele, Cait E., Hardison, Ross C., Olson, Thomas L., Tan, Su-Fern, Feith, David J., Ratan, Aakrosh, and Loughran, Thomas P.

Abstract

Large granular lymphocyte (LGL) leukemia comprises a group of rare lymphoproliferative disorders whose molecular landscape is incompletely defined. We leveraged paired whole exome and transcriptome sequencing in the largest LGL leukemia cohort to date, which included 105 patients (93 TCRαβ T-LGL and 12 TCRγδ T-LGL). 76 mutations were observed in three or more patients in the cohort, and out of those, STAT3, KMT2D PIK3R1, TTN, EYS, and SULF1mutations were shared between both subtypes. We identified ARHGAP25, ABCC9, PCDHA11, SULF1, SLC6A15, DDX59, DNMT3A, FAS, KDM6A, KMT2D, PIK3R1, STAT3, STAT5B, TET2, and TNFAIP3as recurrently mutated putative drivers using an unbiased driver analysis approach leveraging our whole exome cohort.Hotspot mutations in STAT3, PIK3R1, and FASwere detected, whereas truncating mutations in epigenetic modifying enzymes such as KMT2Dand TET2were observed. Moreover, STAT3mutations co-occurred with mutations in chromatin and epigenetic modifying genes, especially KMT2Dand SETD1B(p< 0.01, p< 0.05 respectively). STAT3was mutated in 50.5% of the patients. Most common Y640F STAT3mutation was associated with lower ANC values, and N647I mutation was associated with lower hemoglobin values. Somatic activating mutations (Q160P, D170Y, L287F) in the STAT3coiled-coil domain were characterized. STAT3mutant patients exhibited increased mutational burden and enrichment of a mutational signature associated with increased spontaneous deamination of 5-methylcytosine. Finally, gene expression analysis revealed enrichment of interferongamma signaling anddecreased PI3K-Akt signaling for STAT3mutant patients. These findings highlight the clinical and molecular heterogeneity of this rare disorder.

Published
2022
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25. Frequent Somatic TET2Mutations in Chronic NK-LGL Leukemia with Distinct Patterns of Cytopenias

Author

Olson, Thomas L., Cheon, HeeJin, Xing, Jeffrey C., Olson, Kristine C., Paila, Umadevi, Hamele, Cait E., Neelamraju, Yaseswini, Shemo, Bryna C., Schmachtenberg, Matt, Sundararaman, Shriram K., Toro, Mariella F., Keller, Cheryl A., Farber, Emily A., Onengut-Gumuscu, Suna, Garrett-Bakelman, Francine E., Hardison, Ross C., Feith, David J., Ratan, Aakrosh, and Loughran, Thomas P

Abstract

Chronic natural killer large granular lymphocyte (NK-LGL) leukemia, also referred to as chronic lymphoproliferative disorder of NK cells (CLPD-NK), is a rare disorder defined by prolonged expansion of clonal NK cells. Similar prevalence of STAT3mutations in chronic T- and NK-LGL leukemia is suggestive of common pathogenesis. We undertook whole genome sequencing to identify mutations unique to NK-LGL leukemia. We analyzed the results to develop a resequencing panel and applied it to 58 patients. PI3K pathway gene mutations (PIK3CD/PIK3AP1) and TNFAIP3mutations were seen in 5% and 10% of patients, respectively. TET2was exceptional in that mutations were present in 16/58 (28%) of patient samples, with evidence that TET2mutations can be dominant and exclusive to the NK compartment. Reduced-representation bisulfite sequencing (RRBS) demonstrated that methylation patterns were significantly altered in TET2-mutant samples. The promoter of TET2and that of PTPRD, a negative regulator of STAT3, were found to be methylated in additional cohort samples, largely confined to the TET2 mutant group. Mutations in STAT3were observed in 19/58 (33%) of patient samples, seven of which had concurrent TET2mutations. Thrombocytopenia and resistance to immunosuppressives were uniquely observed in those patients with only TET2mutation (Games-Howell p=0.0074, Fisher’s exact p=0.00466, respectively). Patients with STAT3mutation, inclusive of those with TET2co-mutation, had lower hematocrit (HCT), hemoglobin (HGB), and absolute neutrophil count (ANC) compared to STAT3wild-type patients (Welch’s t-test, p<=0.015). We present the discovery of TET2mutations in chronic NK-LGL leukemia and evidence that it identifies a unique molecular subtype.

Published
2021
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26. Dissecting neural differentiation regulatory networks through epigenetic footprinting

Author

Hongcang Gu, Alexander Meissner, Davide Cacchiarelli, Yakey Yaffe, Alexander M. Tsankov, Reuven Edri, Jeffrey C. Xing, Charles B. Epstein, Michael J. Ziller, John L. Rinn, Julie Donaghey, Casey A. Gifford, Tarjei S. Mikkelsen, Robbyn Issner, Oliver Kohlbacher, Bradley E. Bernstein, Ramona Pop, Alon Goren, Yechiel Elkabetz, Andreas Gnirke, William Mallard, Ziller, Michael J., Edri, Reuven, Yaffe, Yakey, Donaghey, Julie, Pop, Ramona, Mallard, William, Issner, Robbyn, Gifford, Casey A., Goren, Alon, Xing, Jeffrey, Gu, Hongcang, Cacchiarelli, Davide, Tsankov, Alexander M., Epstein, Charle, Rinn, John L., Mikkelsen, Tarjei S., Kohlbacher, Oliver, Gnirke, Andrea, Bernstein, Bradley E., Elkabetz, Yechiel, and Meissner, Alexander

Subjects
Epigenomics, Epigenomic, Transcription, Genetic, Transcription Factor, Cellular differentiation, Reproducibility of Result, Biology, Article, Epigenesis, Genetic, Neural Stem Cells, Embryonic Stem Cell, Humans, Cell Lineage, Neural Stem Cell, Progenitor cell, RNA, Small Interfering, Induced pluripotent stem cell, Embryonic Stem Cells, Genetics, Binding Sites, Multidisciplinary, Binding Site, Reproducibility of Results, Cell Differentiation, Embryonic stem cell, Neural stem cell, Stem cell, Neural development, Neuroscience, Transcription Factors, Human embryonic stem cell line, Human
Abstract

Human pluripotent stem cell derived models that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signaling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells (NPCs) in the embryonic and adult nervous system1-3. This can be exploited to isolate distinct populations of human embryonic stem (ES) cell derived NPCs4. Here, we report the transcriptional and epigenomic analysis of six consecutive stages derived from a HES5-GFP reporter ES cell line5 differentiated along the neural trajectory aimed at modeling key cell fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect the regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell state transition based on the progressive remodeling of the epigenetic landscape and then validated these through a pooled shRNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and show here that they are mediated by combinations of core and stage- specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.

Published
2015

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