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49 results on '"Obeng, Esther A."'

1. Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

Author

Kamens, Jennifer L., Nance, Stephanie, Koss, Cary, Xu, Beisi, Cotton, Anitria, Lam, Jeannie W., Garfinkle, Elizabeth A. R., Nallagatla, Pratima, Smith, Amelia M. R., Mitchell, Sharnise, Ma, Jing, Currier, Duane, Wright, William C., Kavdia, Kanisha, Pagala, Vishwajeeth R., Kim, Wonil, Wallace, LaShanale M., Cho, Ji-Hoon, Fan, Yiping, Seth, Aman, Twarog, Nathaniel, Choi, John K., Obeng, Esther A., Hatley, Mark E., Metzger, Monika L., Inaba, Hiroto, Jeha, Sima, Rubnitz, Jeffrey E., Peng, Junmin, Chen, Taosheng, Shelat, Anang A., Guy, R. Kiplin, and Gruber, Tanja A.

Published
2023
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2. Author Correction: Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

Author

Kamens, Jennifer L., Nance, Stephanie, Koss, Cary, Xu, Beisi, Cotton, Anitria, Lam, Jeannie W., Garfinkle, Elizabeth A. R., Nallagatla, Pratima, Smith, Amelia M. R., Mitchell, Sharnise, Ma, Jing, Currier, Duane, Wright, William C., Kavdia, Kanisha, Pagala, Vishwajeeth R., Kim, Wonil, Wallace, LaShanale M., Cho, Ji-Hoon, Fan, Yiping, Seth, Aman, Twarog, Nathaniel, Choi, John K., Obeng, Esther A., Hatley, Mark E., Metzger, Monika L., Inaba, Hiroto, Jeha, Sima, Rubnitz, Jeffrey E., Peng, Junmin, Chen, Taosheng, Shelat, Anang A., Guy, R. Kiplin, and Gruber, Tanja A.

Published
2023
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4. An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia

Author

Lasry, Audrey, Nadorp, Bettina, Fornerod, Maarten, Nicolet, Deedra, Wu, Huiyun, Walker, Christopher J., Sun, Zhengxi, Witkowski, Matthew T., Tikhonova, Anastasia N., Guillamot-Ruano, Maria, Cayanan, Geraldine, Yeaton, Anna, Robbins, Gabriel, Obeng, Esther A., Tsirigos, Aristotelis, Stone, Richard M., Byrd, John C., Pounds, Stanley, Carroll, William L., Gruber, Tanja A., Eisfeld, Ann-Kathrin, and Aifantis, Iannis

Published
2023
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6. SF3B1 mutation and ATM deletion codrive leukemogenesis via centromeric R-loop dysregulation

Author

Cusan, Martina, Shen, Haifeng, Zhang, Bo, Liao, Aijun, Yang, Lu, Jin, Meiling, Fernandez, Mike, Iyer, Prajish, Wu, Yiming, Hart, Kevyn, Gutierrez, Catherine, Nik, Sara, Pruett-Miller, Shondra M., Stark, Jeremy, Obeng, Esther A., Bowman, Teresa V., Wu, Catherine J., Lin, Ren-Jang, and Wang, Lili

Subjects
Thermo Fisher Scientific Inc., Genes -- Genetic aspects, B cells -- Genetic aspects, RNA -- Genetic aspects, Health care industry
Abstract

RNA splicing factor SF3B1 is recurrently mutated in various cancers, particularly in hematologic malignancies. We previously reported that coexpression of Sf3b1 mutation and Atm deletion in B cells, but not either lesion alone, leads to the onset of chronic lymphocytic leukemia (CLL) with CLL cells harboring chromosome amplification. However, the exact role of Sf3b1 mutation and Atm deletion in chromosomal instability (CIN) remains unclear. Here, we demonstrated that SF3B1 mutation promotes centromeric R-loop (cen-R-loop) accumulation, leading to increased chromosome oscillation, impaired chromosome segregation, altered spindle architecture, and aneuploidy, which could be alleviated by removal of cen-R- loop and exaggerated by deletion of ATM. Aberrant splicing of key genes involved in R-loop processing underlay augmentation of cen-R-loop, as overexpression of the normal isoform, but not the altered form, mitigated mitotic stress in SF3B1-mutant cells. Our study identifies a critical role of splice variants in linking RNA splicing dysregulation and CIN and highlights cen-R-loop augmentation as a key mechanism for leukemogenesis., Introduction Cancer genome sequencing has identified high-frequency mutations of splicing factor SF3B1 in hematologic malignancies such as myelodysplastic syndrome and chronic lymphocytic leukemia (CLL) (1-3). As one of the most [...]

Published
2023
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7. Engineering naturally occurring CD7− T cells for the immunotherapy of hematological malignancies

Author

Freiwan, Abdullah, Zoine, Jaquelyn T., Crawford, Jeremy Chase, Vaidya, Abishek, Schattgen, Stefan A., Myers, Jacquelyn A., Patil, Sagar L., Khanlari, Mahsa, Inaba, Hiroto, Klco, Jeffery M., Mullighan, Charles G., Krenciute, Giedre, Chockley, Peter J., Naik, Swati, Langfitt, Deanna M., Mamonkin, Maksim, Obeng, Esther A., Thomas, Paul G., Gottschalk, Stephen, and Velasquez, M. Paulina

Published
2022
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9. Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL

Author

Talleur, Aimee C., Qudeimat, Amr, Métais, Jean-Yves, Langfitt, Deanna, Mamcarz, Ewelina, Crawford, Jeremy Chase, Huang, Sujuan, Cheng, Cheng, Hurley, Caitlin, Madden, Renee, Sharma, Akshay, Suliman, Ali, Srinivasan, Ashok, Velasquez, M. Paulina, Obeng, Esther A., Willis, Catherine, Akel, Salem, Karol, Seth E., Inaba, Hiroto, Bragg, Allison, Zheng, Wenting, Zhou, Sheng M., Schell, Sarah, Tuggle-Brown, MaCal, Cullins, David, Patil, Sagar L, Li, Ying, Thomas, Paul G., Zebley, Caitlin, Youngblood, Benjamin, Pui, Ching-Hon, Lockey, Timothy, Geiger, Terrence L., Meagher, Michael M., Triplett, Brandon M., and Gottschalk, Stephen

Published
2022
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11. Author Correction: An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia

Author

Lasry, Audrey, Nadorp, Bettina, Fornerod, Maarten, Nicolet, Deedra, Wu, Huiyun, Walker, Christopher J., Sun, Zhengxi, Witkowski, Matthew T., Tikhonova, Anastasia N., Guillamot-Ruano, Maria, Cayanan, Geraldine, Yeaton, Anna, Robbins, Gabriel, Obeng, Esther A., Tsirigos, Aristotelis, Stone, Richard M., Byrd, John C., Pounds, Stanley, Carroll, William L., Gruber, Tanja A., Eisfeld, Ann-Kathrin, and Aifantis, Iannis

Published
2023
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12. Memory T-cell enriched haploidentical transplantation with NK cell addback results in promising long-term outcomes: a phase II trial.

Author

Naik, Swati, Li, Ying, Talleur, Aimee C., Selukar, Subodh, Ashcraft, Emily, Cheng, Cheng, Madden, Renee M., Mamcarz, Ewelina, Qudeimat, Amr, Sharma, Akshay, Srinivasan, Ashok, Suliman, Ali Y., Epperly, Rebecca, Obeng, Esther A., Velasquez, M. Paulina, Langfitt, Deanna, Schell, Sarah, Métais, Jean-Yves, Arnold, Paula Y., and Hijano, Diego R.

Subjects
IMMUNOLOGIC memory, KILLER cells, CELL transplantation, CHILD patients, HEMATOLOGIC malignancies
Abstract

Background: Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen. Methods: In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy. Results: The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72–98) and 88% (95% CI: 67–96); ≥ CR2 were 81% (95% CI: 61–92) and 68% (95% CI: 47–82) and refractory disease were 32% (95% CI: 11–54) and 20% (95% CI: 6–40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64–87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035). Conclusion: The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611). [ABSTRACT FROM AUTHOR]

Published
2024
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14. SF3B1 mutation and ATM deletion co-drive leukemogenesis via centromeric R-loop dysregulation

Author

Cusan, Martina, primary, Shen, Haifeng, additional, Zhang, Bo, additional, Liao, Aijun, additional, Yang, Lu, additional, Jin, Meiling, additional, Fernandez, Mike, additional, Iyer, Prajish, additional, Wu, Yiming, additional, Hart, Kevyn L., additional, Gutierrez, Catherine, additional, Nik, Sara, additional, Pruett-Miller, Shondra M., additional, Stark, Jeremy, additional, Obeng, Esther A., additional, Bowman, Teresa V., additional, Wu, Catherine J., additional, Lin, Ren-Jang, additional, and Wang, Lili, additional

Published
2023
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15. Supplementary Excel Tables from Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators

Author

Fornerod, Maarten, primary, Ma, Jing, primary, Noort, Sanne, primary, Liu, Yu, primary, Walsh, Michael P., primary, Shi, Lei, primary, Nance, Stephanie, primary, Liu, Yanling, primary, Wang, Yuanyuan, primary, Song, Guangchun, primary, Lamprecht, Tamara, primary, Easton, John, primary, Mulder, Heather L., primary, Yergeau, Donald, primary, Myers, Jacquelyn, primary, Kamens, Jennifer L., primary, Obeng, Esther A., primary, Pigazzi, Martina, primary, Jarosova, Marie, primary, Kelaidi, Charikleia, primary, Polychronopoulou, Sophia, primary, Lamba, Jatinder K., primary, Baker, Sharyn D., primary, Rubnitz, Jeffrey E., primary, Reinhardt, Dirk, primary, van den Heuvel-Eibrink, Marry M., primary, Locatelli, Franco, primary, Hasle, Henrik, primary, Klco, Jeffery M., primary, Downing, James R., primary, Zhang, Jinghui, primary, Pounds, Stanley, primary, Zwaan, C. Michel, primary, and Gruber, Tanja A., primary

Published
2023
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16. Supplementary Tables and Figures from Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators

Author

Fornerod, Maarten, primary, Ma, Jing, primary, Noort, Sanne, primary, Liu, Yu, primary, Walsh, Michael P., primary, Shi, Lei, primary, Nance, Stephanie, primary, Liu, Yanling, primary, Wang, Yuanyuan, primary, Song, Guangchun, primary, Lamprecht, Tamara, primary, Easton, John, primary, Mulder, Heather L., primary, Yergeau, Donald, primary, Myers, Jacquelyn, primary, Kamens, Jennifer L., primary, Obeng, Esther A., primary, Pigazzi, Martina, primary, Jarosova, Marie, primary, Kelaidi, Charikleia, primary, Polychronopoulou, Sophia, primary, Lamba, Jatinder K., primary, Baker, Sharyn D., primary, Rubnitz, Jeffrey E., primary, Reinhardt, Dirk, primary, van den Heuvel-Eibrink, Marry M., primary, Locatelli, Franco, primary, Hasle, Henrik, primary, Klco, Jeffery M., primary, Downing, James R., primary, Zhang, Jinghui, primary, Pounds, Stanley, primary, Zwaan, C. Michel, primary, and Gruber, Tanja A., primary

Published
2023
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17. Data from Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators

Author

Fornerod, Maarten, primary, Ma, Jing, primary, Noort, Sanne, primary, Liu, Yu, primary, Walsh, Michael P., primary, Shi, Lei, primary, Nance, Stephanie, primary, Liu, Yanling, primary, Wang, Yuanyuan, primary, Song, Guangchun, primary, Lamprecht, Tamara, primary, Easton, John, primary, Mulder, Heather L., primary, Yergeau, Donald, primary, Myers, Jacquelyn, primary, Kamens, Jennifer L., primary, Obeng, Esther A., primary, Pigazzi, Martina, primary, Jarosova, Marie, primary, Kelaidi, Charikleia, primary, Polychronopoulou, Sophia, primary, Lamba, Jatinder K., primary, Baker, Sharyn D., primary, Rubnitz, Jeffrey E., primary, Reinhardt, Dirk, primary, van den Heuvel-Eibrink, Marry M., primary, Locatelli, Franco, primary, Hasle, Henrik, primary, Klco, Jeffery M., primary, Downing, James R., primary, Zhang, Jinghui, primary, Pounds, Stanley, primary, Zwaan, C. Michel, primary, and Gruber, Tanja A., primary

Published
2023
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18. Supplementary table 1 from Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations

Author

Cheruiyot, Abigael, primary, Li, Shan, primary, Nonavinkere Srivatsan, Sridhar, primary, Ahmed, Tanzir, primary, Chen, Yuhao, primary, Lemacon, Delphine S., primary, Li, Ying, primary, Yang, Zheng, primary, Wadugu, Brian A., primary, Warner, Wayne A., primary, Pruett-Miller, Shondra M., primary, Obeng, Esther A., primary, Link, Daniel C., primary, He, Dalin, primary, Xiao, Fei, primary, Wang, Xiaowei, primary, Bailis, Julie M., primary, Walter, Matthew J., primary, and You, Zhongsheng, primary

Published
2023
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19. Supplementary table 3 from Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations

Author

Cheruiyot, Abigael, primary, Li, Shan, primary, Nonavinkere Srivatsan, Sridhar, primary, Ahmed, Tanzir, primary, Chen, Yuhao, primary, Lemacon, Delphine S., primary, Li, Ying, primary, Yang, Zheng, primary, Wadugu, Brian A., primary, Warner, Wayne A., primary, Pruett-Miller, Shondra M., primary, Obeng, Esther A., primary, Link, Daniel C., primary, He, Dalin, primary, Xiao, Fei, primary, Wang, Xiaowei, primary, Bailis, Julie M., primary, Walter, Matthew J., primary, and You, Zhongsheng, primary

Published
2023
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20. Supplementary figures and legends from Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations

Author

Cheruiyot, Abigael, primary, Li, Shan, primary, Nonavinkere Srivatsan, Sridhar, primary, Ahmed, Tanzir, primary, Chen, Yuhao, primary, Lemacon, Delphine S., primary, Li, Ying, primary, Yang, Zheng, primary, Wadugu, Brian A., primary, Warner, Wayne A., primary, Pruett-Miller, Shondra M., primary, Obeng, Esther A., primary, Link, Daniel C., primary, He, Dalin, primary, Xiao, Fei, primary, Wang, Xiaowei, primary, Bailis, Julie M., primary, Walter, Matthew J., primary, and You, Zhongsheng, primary

Published
2023
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21. Supplementary methods from Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations

Author

Cheruiyot, Abigael, primary, Li, Shan, primary, Nonavinkere Srivatsan, Sridhar, primary, Ahmed, Tanzir, primary, Chen, Yuhao, primary, Lemacon, Delphine S., primary, Li, Ying, primary, Yang, Zheng, primary, Wadugu, Brian A., primary, Warner, Wayne A., primary, Pruett-Miller, Shondra M., primary, Obeng, Esther A., primary, Link, Daniel C., primary, He, Dalin, primary, Xiao, Fei, primary, Wang, Xiaowei, primary, Bailis, Julie M., primary, Walter, Matthew J., primary, and You, Zhongsheng, primary

Published
2023
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22. Supplementary table 2 from Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations

Author

Cheruiyot, Abigael, primary, Li, Shan, primary, Nonavinkere Srivatsan, Sridhar, primary, Ahmed, Tanzir, primary, Chen, Yuhao, primary, Lemacon, Delphine S., primary, Li, Ying, primary, Yang, Zheng, primary, Wadugu, Brian A., primary, Warner, Wayne A., primary, Pruett-Miller, Shondra M., primary, Obeng, Esther A., primary, Link, Daniel C., primary, He, Dalin, primary, Xiao, Fei, primary, Wang, Xiaowei, primary, Bailis, Julie M., primary, Walter, Matthew J., primary, and You, Zhongsheng, primary

Published
2023
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24. 3138 – EPIGENETIC REGULATORS TET2 AND POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) COORDINATE GENE EXPRESSION IN MYELODYSPLASTIC SYNDROME (MDS)

Author

Myers, Jacquelyn, primary, Henriet, Elodie, additional, Wallace, LaShanale, additional, Metidji, Amina, additional, Skorupa, Jordan, additional, Leal-Cervantes, Ana, additional, Pruett-Miller, Shondra, additional, Fan, Yiping, additional, Iacobucci, Ilaria, additional, Haferlach, Torsten, additional, Mullighan, Charles, additional, and Obeng, Esther, additional

Published
2023
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25. An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia

Author

Lasry, Audrey, primary, Nadorp, Bettina, additional, Fornerod, Maarten, additional, Nicolet, Deedra, additional, Wu, Huiyun, additional, Walker, Christopher J., additional, Sun, Zhengxi, additional, Witkowski, Matthew T., additional, Tikhonova, Anastasia N., additional, Guillamot-Ruano, Maria, additional, Cayanan, Geraldine, additional, Yeaton, Anna, additional, Robbins, Gabriel, additional, Obeng, Esther A., additional, Tsirigos, Aristotelis, additional, Stone, Richard M., additional, Byrd, John C., additional, Pounds, Stanley, additional, Carroll, William L., additional, Gruber, Tanja A., additional, Eisfeld, Ann-Kathrin, additional, and Aifantis, Iannis, additional

Published
2022
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26. Venetoclax-based therapy as a bridge to allogeneic hematopoietic cell transplantation in children with relapsed/refractory AML

Author

Pfeiffer, Thomas, primary, Li, Ying, additional, Ashcraft, Emily, additional, Karol, Seth E., additional, Rubnitz, Jeffrey E., additional, Epperly, Rebecca, additional, Madden, Renee, additional, Mamcarz, Ewelina, additional, Obeng, Esther, additional, Qudeimat, Amr, additional, Sharma, Akshay, additional, Srinivasan, Ashok, additional, Suliman, Ali, additional, Talleur, Aimee C., additional, Velasquez, M. Paulina, additional, Gottschalk, Stephen, additional, Triplett, Brandon M., additional, and Naik, Swati, additional

Published
2022
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29. CD45RA Depleted T-Cell Addback and Prophylactic Blinatumomab Administration Following Tcrαβ/CD19-Depleted Haploidentical Transplantation in Pediatric Patients with High Risk Acute Leukemia

Author

Naik, Swati, primary, Li, Ying, additional, Madden, Renee, additional, Mamcarz, Ewelina, additional, Srinivasan, Ashok, additional, Sharma, Akshay, additional, Talleur, Aimee C, additional, Qudeimat, Amr, additional, Suliman, Ali, additional, Epperly, Rebecca, additional, Obeng, Esther A, additional, Velasquez, Mireya Paulina, additional, Hijano, Diego, additional, Marón, Gabriela M., additional, Metais, Jean-Yves, additional, Gottschalk, Stephen, additional, and Triplett, Brandon M., additional

Published
2022
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30. CD45RA-Depleted Haploidentical Transplantation Combined with NK Cell Addback Results in Promising Long-Term Outcomes in Pediatric Patients with High-Risk Hematologic Malignancies

Author

Naik, Swati, primary, Talleur, Aimee C, additional, Li, Ying, additional, Madden, Renee, additional, Mamcarz, Ewelina, additional, Qudeimat, Amr, additional, Sharma, Akshay, additional, Srinivasan, Ashok, additional, Suliman, Ali, additional, Epperly, Rebecca, additional, Obeng, Esther A, additional, Velasquez, Mireya Paulina, additional, Hijano, Diego, additional, Marón, Gabriela M., additional, Metais, Jean-Yves, additional, Gottschalk, Stephen, additional, and Triplett, Brandon M., additional

Published
2022
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31. Venetoclax-Based Combination Therapy As a Bridge to Allogeneic Hematopoietic Stem Cell Transplant in Children with Relapsed/Refractory AML

Author

Pfeiffer, Thomas, primary, Li, Ying, additional, Karol, Seth E, additional, Rubnitz, Jeffrey E, additional, Epperly, Rebecca, additional, Madden, Renee, additional, Mamcarz, Ewelina, additional, Obeng, Esther A, additional, Qudeimat, Amr, additional, Sharma, Akshay, additional, Srinivasan, Ashok, additional, Suliman, Ali, additional, Talleur, Aimee C, additional, Velasquez, Mireya Paulina, additional, Gottschalk, Stephen, additional, Triplett, Brandon M., additional, and Naik, Swati, additional

Published
2022
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36. CD45RA-Depleted Haploidentical Transplantation Combined with NK Cell Addback Results in Promising Long-Term Outcomes in Pediatric Patients with High-Risk Hematologic Malignancies

Author

Naik, Swati, primary, Talleur, Aimee C, additional, Li, Ying, additional, Madden, Renee M., additional, Mamcarz, Ewelina, additional, Qudeimat, Amr, additional, Sharma, Akshay, additional, Srinivasan, Ashok, additional, Suliman, Ali Y, additional, Epperly, Rebecca, additional, Obeng, Esther A., additional, Velasquez, Mireya Paulina, additional, Hijano, Diego, additional, Maron, Gabriela, additional, Gottschalk, Stephen, additional, and Triplett, Brandon M, additional

Published
2021
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37. CD45RO+ T-Cell Add Back and Prophylactic Blinatumomab Administration Post Tcrαβ/CD19-Depleted Haploidentical Transplantation in Pediatric Patients with High Risk Acute Leukemia

Author

Naik, Swati, primary, Madden, Renee M., additional, Mamcarz, Ewelina, additional, Srinivasan, Ashok, additional, Sharma, Akshay, additional, Talleur, Aimee C, additional, Epperly, Rebecca, additional, Qudeimat, Amr, additional, Suliman, Ali Y, additional, Obeng, Esther A., additional, Velasquez, Mireya Paulina, additional, Hijano, Diego, additional, Maron, Gabriela, additional, Li, Ying, additional, Gottschalk, Stephen, additional, and Triplett, Brandon M, additional

Published
2021
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38. Selective Targeting of Splicing Factor Mutant Hematopoietic Stem and Progenitor Cells Via STAT3 Inhibition

Author

Potts, Kathryn S, primary, Cameron, Rosannah C., additional, Ghazale, Noura, additional, Gupta, Varun, additional, Barajas, Juan Martin, additional, Wallace, LaShanale, additional, Leal-Cervantes, Ana, additional, Aluri, Srinivas, additional, Pradhan, Kith, additional, McKinstry, Mia, additional, Bai, Xiaoying, additional, Choudhary, Gaurav S, additional, Shastri, Aditi, additional, Verma, Amit, additional, Obeng, Esther A., additional, and Bowman, Teresa V., additional

Published
2021
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39. Integrative Genomic Analysis of Pediatric Myeloid-Related Acute Leukemias Identifies Novel Subtypes and Prognostic Indicators

Author

Fornerod, Maarten, primary, Ma, Jing, additional, Noort, Sanne, additional, Liu, Yu, additional, Walsh, Michael P., additional, Shi, Lei, additional, Nance, Stephanie, additional, Liu, Yanling, additional, Wang, Yuanyuan, additional, Song, Guangchun, additional, Lamprecht, Tamara, additional, Easton, John, additional, Mulder, Heather L., additional, Yergeau, Donald, additional, Myers, Jacquelyn, additional, Kamens, Jennifer L., additional, Obeng, Esther A., additional, Pigazzi, Martina, additional, Jarosova, Marie, additional, Kelaidi, Charikleia, additional, Polychronopoulou, Sophia, additional, Lamba, Jatinder K., additional, Baker, Sharyn D., additional, Rubnitz, Jeffrey E., additional, Reinhardt, Dirk, additional, van den Heuvel-Eibrink, Marry M., additional, Locatelli, Franco, additional, Hasle, Henrik, additional, Klco, Jeffery M., additional, Downing, James R., additional, Zhang, Jinghui, additional, Pounds, Stanley, additional, Zwaan, C. Michel, additional, and Gruber, Tanja A., additional

Published
2021
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40. Engineering naturally occurring CD7−T cells for the immunotherapy of hematological malignancies

Author

Freiwan, Abdullah, Zoine, Jaquelyn T., Crawford, Jeremy Chase, Vaidya, Abishek, Schattgen, Stefan A., Myers, Jacquelyn A., Patil, Sagar L., Khanlari, Mahsa, Inaba, Hiroto, Klco, Jeffery M., Mullighan, Charles G., Krenciute, Giedre, Chockley, Peter J., Naik, Swati, Langfitt, Deanna M., Mamonkin, Maksim, Obeng, Esther A., Thomas, Paul G., Gottschalk, Stephen, and Velasquez, M. Paulina

Abstract

•Naturally occurring CD7 negative T cells are functional effector T cells that can be used for chimeric antigen receptor therapy.•CD7 negative T cells expressing a CD7-CAR have robust antitumor activity and bypass fratricide.

Published
2022
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42. 128 - CD45RA-Depleted Haploidentical Transplantation Combined with NK Cell Addback Results in Promising Long-Term Outcomes in Pediatric Patients with High-Risk Hematologic Malignancies

Author

Naik, Swati, Talleur, Aimee C, Li, Ying, Madden, Renee, Mamcarz, Ewelina, Qudeimat, Amr, Sharma, Akshay, Srinivasan, Ashok, Suliman, Ali, Epperly, Rebecca, Obeng, Esther A, Velasquez, Mireya Paulina, Hijano, Diego, Marón, Gabriela M., Metais, Jean-Yves, Gottschalk, Stephen, and Triplett, Brandon M.

Published
2022
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43. 41 - CD45RA Depleted T-Cell Addback and Prophylactic Blinatumomab Administration Following Tcrαβ/CD19-Depleted Haploidentical Transplantation in Pediatric Patients with High Risk Acute Leukemia

Author

Naik, Swati, Li, Ying, Madden, Renee, Mamcarz, Ewelina, Srinivasan, Ashok, Sharma, Akshay, Talleur, Aimee C, Qudeimat, Amr, Suliman, Ali, Epperly, Rebecca, Obeng, Esther A, Velasquez, Mireya Paulina, Hijano, Diego, Marón, Gabriela M., Metais, Jean-Yves, Gottschalk, Stephen, and Triplett, Brandon M.

Published
2022
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44. Hematopoietic Stem Cells from Mice and Individuals with Sickle Cell Disease Display Premature Senescence and Loss of Function That Is Targetable By Senolytic Therapy

Author

Barve, Aditya, Dabbah, Mahmoud, Kooienga, Emilia, Obeng, Esther A., Myers, Jacquelyn, Sharma, Akshay, and McKinney-Freeman, Shannon

Abstract

Sickle cell disease (SCD) is an inherited anemia caused by mutations in the β-globin gene, resulting in aberrant hemoglobin polymerization driving hemolysis, vasooclusion, and systemic inflammation. Allogeneic hematopoietic stem cell (HSC) transplantation is potentially curative, and novel autologous therapies involving gene-editing of mobilized HSCs are being developed. However, many SCD patients are unable to undergo autologous gene-editing due to failure to mobilize sufficient numbers of HSCs. Further, the damaging effects of SCD on the HSC pool remain uncharacterized. Therefore, we interrogated young and aged cohorts of humanized SCD mice and non-SCD controls for HSC frequency and function. Immunophenotypic HSC frequency was mildly elevated (1.3-fold, p=0.00316) in 2-month-old SCD mice, relative to controls (n=5-6/group). In contrast, HSC numbers were halved in 6 and 12-month-old SCD mice (n=8-10/group, p=0.00358 and p=0.0148, respectively). Competitive transplantation of whole bone marrow (WBM) from 2 and 6-month-old SCD mice displayed a profound loss of peripheral blood repopulation, relative to age-matched control mice. Quantitative limiting dilution transplantation of WBM from 2 and 6-month-old SCD mice revealed a 4 and 6-fold loss of functional HSCs, relative to control mice. Thus, despite elevated numbers of phenotypic HSCs in young SCD mice, the HSC pool is depleted of functional repopulating cells during SCD. To understand the loss of functional HSCs, we performed bulk RNA-sequencing of purified HSCs from 6-month-old SCD mice. We observed downregulation of 37 genes encoding ribosomal and histone proteins, suggesting impaired histone/ribosome biogenesis, a phenotype associated with senescence. Consistently, pathway enrichment analysis also revealed perturbed p53 activity and a high degree of association with published molecular signatures of senescence.

Published
2023
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45. Regulation of Alternative Splicing in B-Cell ALL By DYRK1A

Author

Jin, Qi, Harris, Ethan, Myers, Jacquelyn A., Cotton, Anitria, Wen, Jeremy, Melo-Cardenas, Johanna, Yoshimi, Akihide, Abdel-Wahab, Omar, Obeng, Esther A., and Crispino, John D.

Abstract

DYRK1A, located in the Down syndrome critical region of chromosome 21, is a serine and threonine kinase that controls multiple cellular processes including apoptosis, cell cycle, transcription and signal transduction. We previously demonstrated that DYRK1A is required for maturation of B cells and is a therapeutic target in B-cell ALL, including both DS and non-DS subtypes. Key substrates within the B-cell lineage include D-type cyclins, FOXO1, and STAT3. Given that several studies have reported that DYRK1A phosphorylates various splicing factors and participates in splicing of Tau in neuronal cells, we investigated the contribution of DYRK1A to splicing in malignant B cells.

Published
2023
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46. SF3B1 K700EAlters the Splicing of Metabolism and Stress Response Genes, Attenuating the Effect of DNMT3A Mutations in MDS

Author

Wallace, Lashanale, Myers, Jacquelyn A., Engelken, Mark, Cullins, David, Sheppard, Heather, and Obeng, Esther A.

Abstract

Myelodysplastic syndromes (MDS) are clonal stem cell disorders associated with low blood counts and a high risk of leukemic transformation. Genomic sequencing studies have demonstrated that MDS develops due to the acquisition of somatic mutations in hematopoietic stem cells (HSCs). Splicing factor 3b subunit 1 ( SF3B1) mutations, one of the most frequent mutations in MDS, are associated with lower-risk disease characterized by ineffective erythropoiesis. Our group and others have shown that mutations in SF3B1 cause aberrant mRNA splicing in human and murine HSCs, an expansion of long-term HSCs (LT-HSCs) in primary mice, but a competitive disadvantage in transplantation assays. DNMT3A, de novomethyltransferase 3A, is an epigenetic regulator mutated in ~10-15% of MDS. DNMT3A mutations are associated with unfavorable outcomes in MDS including a higher risk of leukemia transformation and shorter overall survival. Murine models of Dnmt3a mutations revealed that Dnmt3a-mutant HSCs have increased self-renewal over lineage-specific differentiation. SF3B1and DNMT3Amutations co-occur more frequently than expected by chance and arise early in MDS pathogenesis, making them attractive therapeutic targets. MDS patients with SF3B1 and DNMT3Amutations have shorter progression-free survival than those with solely SF3B1mutations. However, the mechanisms by which these mutations cooperate to cause HSC dysfunction and their possible combined role in leukemogenesis are not well understood.

Published
2023
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47. Preferential expansion of CD8+CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL

Author

Talleur, Aimee C., Qudiemat, Amr, Métais, Jean-Yves, Langfitt, Deanna, Mamcarz, Ewelina, Crawford, Jeremy Chase, Huang, Sujuan, Cheng, Cheng, Hurley, Caitlin, Madden, Renee, Sharma, Akshay, Suliman, Ali, Srinivasan, Ashok, Velasquez, Paulina, Obeng, Esther, Willis, Catherine, Akel, Salem, Karol, Seth E., Inaba, Hiroto, Bragg, Allison, Zheng, Wenting, Zhou, Sheng, Schell, Sarah, Tuggle-Brown, MaCal, Cullins, David, Patil, Sagar L, Li, Ying, Thomas, Paul G., Zebley, Caitlin, Youngblood, Benjamin, Pui, Ching-Hong, Lockey, Timothy, Geiger, Terrence L., Meagher, Michael, Triplett, Brandon M., and Gottschalk, Stephen

Abstract

T cells expressing CD19-specific chimeric antigen receptors (CD19-CARs) have potent antileukemia activity in pediatric and adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, not all patients achieve a complete response (CR), and a significant percentage relapse after CD19-CAR T-cell therapy due to T-cell intrinsic and/or extrinsic mechanisms. Thus, there is a need to evaluate new CD19-CAR T-cell products in patients to improve efficacy. We developed a Phase 1/2 clinical study to evaluate an institutional autologous CD19-CAR T-cell product in pediatric patients with relapsed/refractory B-ALL. Here we report the outcome of the phase 1 study participants (n=12). Treatment was well tolerated, with low incidence of both cytokine release syndrome (any grade, n=6) and neurotoxicity (any grade, n=3). Nine out of 12 patients (75%) achieved a minimal residual disease-negative CR in the bone marrow. High disease burden (≥40% morphologic blasts) prior to CAR T-cell infusion correlated with increased side effects and lower response rate, but not with CD19-CAR T-cell expansion. Postinfusion, CD8+CAR T cells had a proliferative advantage over CD4+CAR T cells, and at peak expansion had an effector memory phenotype with evidence of antigen-driven differentiation. Patients that proceeded to allogeneic hematopoietic cell transplantation had sustained, durable responses. In summary, initial evaluation of our institutional CD19-CAR T-cell product demonstrates safety and efficacy, while highlighting the impact of pre-infusion disease burden on outcomes. This trial was registered at www.clinicaltrials.govas #NCT03573700.

Published
2022
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48. Noncoding rules of survival: epigenetic regulation of normal and malignant hematopoiesis.

Author

Wallace L and Obeng EA

Abstract

Hematopoiesis is an essential process for organismal development and homeostasis. Epigenetic regulation of gene expression is critical for stem cell self-renewal and differentiation in normal hematopoiesis. Increasing evidence shows that disrupting the balance between self-renewal and cell fate decisions can give rise to hematological diseases such as bone marrow failure and leukemia. Consequently, next-generation sequencing studies have identified various aberrations in histone modifications, DNA methylation, RNA splicing, and RNA modifications in hematologic diseases. Favorable outcomes after targeting epigenetic regulators during disease states have further emphasized their importance in hematological malignancy. However, these targeted therapies are only effective in some patients, suggesting that further research is needed to decipher the complexity of epigenetic regulation during hematopoiesis. In this review, an update on the impact of the epigenome on normal hematopoiesis, disease initiation and progression, and current therapeutic advancements will be discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wallace and Obeng.)

Published
2023
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49. Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations.

Author

Cheruiyot A, Li S, Nonavinkere Srivatsan S, Ahmed T, Chen Y, Lemacon DS, Li Y, Yang Z, Wadugu BA, Warner WA, Pruett-Miller SM, Obeng EA, Link DC, He D, Xiao F, Wang X, Bailis JM, Walter MJ, and You Z

Subjects
Cell Cycle, Cell Line, Tumor, Chromosomal Instability, Fluorescent Dyes, Gene Expression Regulation, Genes, Reporter, Genome-Wide Association Study, Humans, K562 Cells, RNA-Binding Proteins, RNA-Seq, Ribonuclease H metabolism, Spliceosomes, Mutation, Myelodysplastic Syndromes metabolism, Nonsense Mediated mRNA Decay, Phosphoproteins genetics, RNA Splicing Factors genetics, Splicing Factor U2AF genetics
Abstract

Nonsense-mediated RNA decay (NMD) is recognized as an RNA surveillance pathway that targets aberrant mRNAs with premature translation termination codons (PTC) for degradation, however, its molecular mechanisms and roles in health and disease remain incompletely understood. In this study, we developed a novel reporter system to accurately measure NMD activity in individual cells. A genome-wide CRISPR-Cas9 knockout screen using this reporter system identified novel NMD-promoting factors, including multiple components of the SF3B complex and other U2 spliceosome factors. Interestingly, cells with mutations in the spliceosome genes SF3B1 and U2AF1 , which are commonly found in myelodysplastic syndrome (MDS) and cancers, have overall attenuated NMD activity. Compared with wild-type (WT) cells, SF3B1- and U2AF1-mutant cells were more sensitive to NMD inhibition, a phenotype that is accompanied by elevated DNA replication obstruction, DNA damage, and chromosomal instability. Remarkably, the sensitivity of spliceosome mutant cells to NMD inhibition was rescued by overexpression of RNase H1, which removes R-loops in the genome. Together, these findings shed new light on the functional interplay between NMD and RNA splicing and suggest a novel synthetic lethal strategy for the treatment of MDS and cancers with spliceosome mutations. SIGNIFICANCE: This study has developed a novel NMD reporter system and identified a potential therapeutic approach of targeting the NMD pathway to treat cancer with spliceosome gene mutations., (©2021 American Association for Cancer Research.)

Published
2021
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