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1. Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma: LYMPHOMA

Author

Shaw, Timothy I., Pounds, Stanley, Cao, Xueyuan, Ma, Jing, Palacios, Gustavo, Mason, John, Perkins, Sherrie, Wu, Gang, Fan, Yiping, Wang, Jian, Zhou, Xin, Obermayer, Alyssa, Kinney, Marsha C., Kraveka, Jacqueline, Gross, Thomas, Sandlund, John, Zhang, Jinghui, Mullighan, Charles, Lim, Megan S., and Leventaki, Vasiliki

Published
2025
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2. A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia

Author

Xu, Jason, Chen, Changya, Sussman, Jonathan H., Yoshimura, Satoshi, Vincent, Tiffaney, Pölönen, Petri, Hu, Jianzhong, Bandyopadhyay, Shovik, Elghawy, Omar, Yu, Wenbao, Tumulty, Joseph, Chen, Chia-hui, Li, Elizabeth Y., Diorio, Caroline, Shraim, Rawan, Newman, Haley, Uppuluri, Lahari, Li, Alexander, Chen, Gregory M., Wu, David W., Ding, Yang-yang, Xu, Jessica A., Karanfilovski, Damjan, Lim, Tristan, Hsu, Miles, Thadi, Anusha, Ahn, Kyung Jin, Wu, Chi-Yun, Peng, Jacqueline, Sun, Yusha, Wang, Alice, Mehta, Rushabh, Frank, David, Meyer, Lauren, Loh, Mignon L., Raetz, Elizabeth A., Chen, Zhiguo, Wood, Brent L., Devidas, Meenakshi, Dunsmore, Kimberly P., Winter, Stuart S., Chang, Ti-Cheng, Wu, Gang, Pounds, Stanley B., Zhang, Nancy R., Carroll, William, Hunger, Stephen P., Bernt, Kathrin, Yang, Jun J., Mullighan, Charles G., Tan, Kai, and Teachey, David T.

Published
2025
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4. Integrated drug resistance and leukemic stemness gene-expression scores predict outcomes in large cohort of over 3500 AML patients from 10 trials

Author

H. Elsayed, Abdelrahman, Cao, Xueyuan, Marrero, Richard J., Nguyen, Nam H. K., Wu, Huiyun, Ni, Yonhui, Ribeiro, Raul C., Tobias, Herold, Valk, Peter J., Béliveau, François, Richard-Carpentier, Guillaume, Hébert, Josée, Zwaan, C. Michel, Gamis, Alan, Kolb, Edward Anders, Aplenc, Richard, Alonzo, Todd A., Meshinchi, Soheil, Rubnitz, Jeffrey, Pounds, Stanley, and Lamba, Jatinder K.

Published
2024
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5. A new genomic framework to categorize pediatric acute myeloid leukemia.

Author

Umeda, Masayuki, Ma, Jing, Westover, Tamara, Ni, Yonghui, Song, Guangchun, Maciaszek, Jamie, Rusch, Michael, Rahbarinia, Delaram, Foy, Scott, Walsh, Michael, Kumar, Priyadarshini, Liu, Yanling, Yang, Wenjian, Fan, Yiping, Wu, Gang, Baker, Sharyn, Ma, Xiaotu, Wang, Lu, Alonzo, Todd, Rubnitz, Jeffrey, Pounds, Stanley, Klco, Jeffery, and Huang, Benjamin

Subjects
Humans, Child, Leukemia, Myeloid, Acute, Mutation, Prognosis, Genomics, Transcription Factors, Repressor Proteins, Tumor Suppressor Proteins
Abstract

Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define the genomic landscape of pAML, we systematically categorized 887 pAML into 23 mutually distinct molecular categories, including new major entities such as UBTF or BCL11B, covering 91.4% of the cohort. These molecular categories were associated with unique expression profiles and mutational patterns. For instance, molecular categories characterized by specific HOXA or HOXB expression signatures showed distinct mutation patterns of RAS pathway genes, FLT3 or WT1, suggesting shared biological mechanisms. We show that molecular categories were strongly associated with clinical outcomes using two independent cohorts, leading to the establishment of a new prognostic framework for pAML based on these updated molecular categories and minimal residual disease. Together, this comprehensive diagnostic and prognostic framework forms the basis for future classification of pAML and treatment strategies.

Published
2024

6. The genomic basis of childhood T-lineage acute lymphoblastic leukaemia

Author

Pölönen, Petri, Di Giacomo, Danika, Seffernick, Anna Eames, Elsayed, Abdelrahman, Kimura, Shunsuke, Benini, Francesca, Montefiori, Lindsey E., Wood, Brent L., Xu, Jason, Chen, Changya, Cheng, Zhongshan, Newman, Haley, Myers, Jason, Iacobucci, Ilaria, Li, Elizabeth, Sussman, Jonathan, Hedges, Dale, Hui, Yawei, Diorio, Caroline, Uppuluri, Lahari, Frank, David, Fan, Yiping, Chang, Yunchao, Meshinchi, Soheil, Ries, Rhonda, Shraim, Rawan, Li, Alexander, Bernt, Kathrin M., Devidas, Meenakshi, Winter, Stuart S., Dunsmore, Kimberly P., Inaba, Hiroto, Carroll, William L., Ramirez, Nilsa C., Phillips, Aaron H., Kriwacki, Richard W., Yang, Jun J., Vincent, Tiffaney L., Zhao, Yaqi, Ghate, Pankaj S., Wang, Jian, Reilly, Colleen, Zhou, Xin, Sanders, Mathijs A., Takita, Junko, Kato, Motohiro, Takasugi, Nao, Chang, Bill H., Press, Richard D., Loh, Mignon, Rampersaud, Evadnie, Raetz, Elizabeth, Hunger, Stephen P., Tan, Kai, Chang, Ti-Cheng, Wu, Gang, Pounds, Stanley B., Mullighan, Charles G., and Teachey, David T.

Published
2024
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8. The St. Jude STEM Clubs: An Afterschool STEM Club for Upper Elementary School Students in Memphis, TN

Author

Ayers, Katherine A., Wade-Jaimes, Katherine, Wang, Lei, Pennella, Robyn A., and Pounds, Stanley B.

Abstract

Informal science, technology, engineering, and math (STEM) programs are important tools for broadening participation in STEM careers. The St. Jude STEM Club (SJSC) is a 10-week afterschool STEM club focused on real-world problems in pediatric cancer research and designed for students in the fifth grade. The SJSC is conducted in partnership with the Shelby County Schools (SCS), an urban school district that encompasses Memphis, TN and serves a disproportionate number of students from underrepresented backgrounds in science. In this report, we provide details on the club logistics, curriculum, pilot data and outcomes related to club impact on student attitudes towards science, and challenges and limitations of the program. Participants in the program reported significantly higher rates of STEM engagement, STEM identity, critical thinking, perseverance, and relationships with peers and adults compared to national normative data. This program description is intended to serve as a resource for other institutions wanting to use a similar strategy to broaden participation in STEM careers.

Published
2020

9. Integrated genomic analysis identifies UBTF tandem duplications as a recurrent lesion in pediatric acute myeloid leukemiaUBTF tandem duplications in pediatric acute myeloid leukemia

Author

Umeda, Masayuki, Ma, Jing, Huang, Benjamin J, Hagiwara, Kohei, Westover, Tamara, Abdelhamed, Sherif, Barajas, Juan M, Thomas, Melvin E, Walsh, Michael P, Song, Guangchun, Tian, Liqing, Liu, Yanling, Chen, Xiaolong, Kolekar, Pandurang, Tran, Quang, Foy, Scott G, Maciaszek, Jamie L, Kleist, Andrew B, Leonti, Amanda R, Ju, Bengsheng, Easton, John, Wu, Huiyun, Valentine, Virginia, Valentine, Marcus B, Liu, Yen-Chun, Ries, Rhonda E, Smith, Jenny L, Parganas, Evan, Iacobucci, Ilaria, Hiltenbrand, Ryan, Miller, Jonathan, Myers, Jason R, Rampersaud, Evadnie, Rahbarinia, Delaram, Rusch, Michael, Wu, Gang, Inaba, Hiroto, Wang, Yi-Cheng, Alonzo, Todd A, Downing, James R, Mullighan, Charles G, Pounds, Stanley, Babu, M Madan, Zhang, Jinghui, Rubnitz, Jeffrey E, Meshinchi, Soheil, Ma, Xiaotu, and Klco, Jeffery M

Subjects
Pediatric Cancer, Pediatric Research Initiative, Clinical Research, Rare Diseases, Cancer, Genetics, Childhood Leukemia, Hematology, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Adult, Child, Chromosome Aberrations, Exons, Genomics, Humans, Leukemia, Myeloid, Acute, Mutation, Recurrence
Abstract

The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.SignificanceWe defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes. See related commentary by Hasserjian and Nardi, p. 173. This article is highlighted in the In This Issue feature, p. 171.

Published
2022

11. 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. The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Author

Gao, Qingsong, Ryan, Sarra L., Iacobucci, Ilaria, Ghate, Pankaj S., Cranston, Ruth E., Schwab, Claire, Elsayed, Abdelrahman H., Shi, Lei, Pounds, Stanley, Lei, Shaohua, Baviskar, Pradyuamna, Pei, Deqing, Cheng, Cheng, Bashton, Matthew, Sinclair, Paul, Bentley, David R., Ross, Mark T., Kingsbury, Zoya, James, Terena, Roberts, Kathryn G., Devidas, Meenakshi, Fan, Yiping, Chen, Wenan, Chang, Ti-Cheng, Wu, Gang, Carroll, Andrew, Heerema, Nyla, Valentine, Virginia, Valentine, Marcus, Yang, Wenjian, Yang, Jun J., Moorman, Anthony V., Harrison, Christine J., and Mullighan, Charles G.

Published
2023
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15. Genome-wide CRISPR/Cas9 screen identifies etoposide response modulators associated with clinical outcomes in pediatric AML

Author

Nguyen, Nam H. K., Rafiee, Roya, Tagmount, Abderrahmane, Sobh, Amin, Loguinov, Alex, de Jesus Sosa, Angelica K., Elsayed, Abdelrahman H., Gbadamosi, Mohammed, Seligson, Nathan, Cogle, Christopher R., Rubnitz, Jeffery, Ribeiro, Raul, Downing, James, Cao, Xueyuan, Pounds, Stanley B., Vulpe, Christopher D., and Lamba, Jatinder K.

Published
2023
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16. The genomic landscape of pediatric acute lymphoblastic leukemia

Author

Brady, Samuel W., Roberts, Kathryn G., Gu, Zhaohui, Shi, Lei, Pounds, Stanley, Pei, Deqing, Cheng, Cheng, Dai, Yunfeng, Devidas, Meenakshi, Qu, Chunxu, Hill, Ashley N., Payne-Turner, Debbie, Ma, Xiaotu, Iacobucci, Ilaria, Baviskar, Pradyuamna, Wei, Lei, Arunachalam, Sasi, Hagiwara, Kohei, Liu, Yanling, Flasch, Diane A., Liu, Yu, Parker, Matthew, Chen, Xiaolong, Elsayed, Abdelrahman H., Pathak, Omkar, Li, Yongjin, Fan, Yiping, Michael, J. Robert, Rusch, Michael, Wilkinson, Mark R., Foy, Scott, Hedges, Dale J., Newman, Scott, Zhou, Xin, Wang, Jian, Reilly, Colleen, Sioson, Edgar, Rice, Stephen V., Pastor Loyola, Victor, Wu, Gang, Rampersaud, Evadnie, Reshmi, Shalini C., Gastier-Foster, Julie, Guidry Auvil, Jaime M., Gesuwan, Patee, Smith, Malcolm A., Winick, Naomi, Carroll, Andrew J., Heerema, Nyla A., Harvey, Richard C., Willman, Cheryl L., Larsen, Eric, Raetz, Elizabeth A., Borowitz, Michael J., Wood, Brent L., Carroll, William L., Zweidler-McKay, Patrick A., Rabin, Karen R., Mattano, Leonard A., Maloney, Kelly W., Winter, Stuart S., Burke, Michael J., Salzer, Wanda, Dunsmore, Kimberly P., Angiolillo, Anne L., Crews, Kristine R., Downing, James R., Jeha, Sima, Pui, Ching-Hon, Evans, William E., Yang, Jun J., Relling, Mary V., Gerhard, Daniela S., Loh, Mignon L., Hunger, Stephen P., Zhang, Jinghui, and Mullighan, Charles G.

Published
2022
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18. Genomic subtyping and therapeutic targeting of acute erythroleukemia

Author

Iacobucci, Ilaria, Wen, Ji, Meggendorfer, Manja, Choi, John K, Shi, Lei, Pounds, Stanley B, Carmichael, Catherine L, Masih, Katherine E, Morris, Sarah M, Lindsley, R Coleman, Janke, Laura J, Alexander, Thomas B, Song, Guangchun, Qu, Chunxu, Li, Yongjin, Payne-Turner, Debbie, Tomizawa, Daisuke, Kiyokawa, Nobutaka, Valentine, Marcus, Valentine, Virginia, Basso, Giuseppe, Locatelli, Franco, Enemark, Eric J, Kham, Shirley KY, Yeoh, Allen EJ, Ma, Xiaotu, Zhou, Xin, Sioson, Edgar, Rusch, Michael, Ries, Rhonda E, Stieglitz, Elliot, Hunger, Stephen P, Wei, Andrew H, To, L Bik, Lewis, Ian D, D’Andrea, Richard J, Kile, Benjamin T, Brown, Anna L, Scott, Hamish S, Hahn, Christopher N, Marlton, Paula, Pei, Deqing, Cheng, Cheng, Loh, Mignon L, Ebert, Benjamin L, Meshinchi, Soheil, Haferlach, Torsten, and Mullighan, Charles G

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Orphan Drug, Cancer, Cancer Genomics, Biotechnology, Human Genome, Childhood Leukemia, Pediatric, Rare Diseases, Hematology, Precision Medicine, Pediatric Cancer, Clinical Research, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Adolescent, Adult, Child, Child, Preschool, Female, Genomics, Homeodomain Proteins, Humans, Infant, Infant, Newborn, Leukemia, Erythroblastic, Acute, Male, Mutation, Myeloid-Lymphoid Leukemia Protein, Nuclear Proteins, Nucleophosmin, Prognosis, Tumor Suppressor Protein p53, Young Adult, fms-Like Tyrosine Kinase 3, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

Published
2019

19. A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia.

Author

Nguyen, Rosa, Wu, Huiyun, Pounds, Stanley, Inaba, Hiroto, Ribeiro, Raul, Cullins, David, Rooney, Barbara, Bell, Teresa, Lacayo, Norman, Heym, Kenneth, Degar, Barbara, Janssen, William, Triplett, Brandon, Pui, Ching-Hon, Leung, Wing, Rubnitz, Jeffrey, and Schiff, Deborah

Subjects
Acute myeloid leukemia, Child, Clinical trial, Natural killer cells, Adolescent, Adoptive Transfer, Antineoplastic Combined Chemotherapy Protocols, Child, Child, Preschool, Consolidation Chemotherapy, Cyclophosphamide, Disease-Free Survival, Drug Administration Schedule, Female, Humans, Infant, Interleukin-2, Killer Cells, Natural, Leukemia, Myeloid, Acute, Male, Transplantation, Haploidentical, Vidarabine
Abstract

Consolidation therapies for children with intermediate- or high-risk acute myeloid leukemia (AML) are urgently needed to achieve higher cure rates while limiting therapy-related toxicities. We determined if adoptive transfer of natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA)-mismatched donors may prolong event-free survival in children with intermediate-risk AML who were in first complete remission after chemotherapy. Patients received cyclophosphamide (Day - 7), fludarabine (Days - 6 through - 2), and subcutaneous interleukin-2 (Days - 1, 1, 3, 5, 7, and 9). Purified, unmanipulated NK cells were infused on Day 0, and NK cell chimerism and phenotyping from peripheral blood were performed on Days 7, 14, 21, and 28. As primary endpoint, the event-free survival was compared to a cohort of 55 patients who completed chemotherapy and were in first complete remission but did not receive NK cells. Donor NK cell kinetics were determined as secondary endpoints. Twenty-one patients (median age at diagnosis, 6.0 years [range, 0.1-15.3 years]) received a median of 12.5 × 106 NK cells/kg (range, 3.6-62.2 × 106 cells/kg) without major side effects. All but 3 demonstrated transient engraftment with donor NK cells (median peak donor chimerism, 4% [range, 0-43%]). KIR-HLA-mismatched NK cells expanded in 17 patients (81%) and contracted in 4 (19%). However, adoptive transfer of NK cells did not decrease the cumulative incidence of relapse (0.393 [95% confidence interval: 0.182-0.599] vs. 0.35 [0.209-0.495]; P = .556) and did not improve event-free (60.7 ± 10.9% vs. 69.1 ± 6.8%; P = .553) or overall survival (84.2 ± 8.5% vs. 79.1 ± 6.6%; P = .663) over chemotherapy alone. The lack of benefit may result from insufficient numbers and limited persistence of alloreactive donor NK cells but does not preclude its potential usefulness during other phases of therapy, or in combination with other immunotherapeutic agents. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT00703820 . Registered 24 June 2008.

Published
2019

21. Molecular classification improves risk assessment in adult BCR-ABL1–negative B-ALL

Author

Paietta, Elisabeth, Roberts, Kathryn G., Wang, Victoria, Gu, Zhaohui, Buck, Georgina A.N., Pei, Deqing, Cheng, Cheng, Levine, Ross L., Abdel-Wahab, Omar, Cheng, Zhongshan, Wu, Gang, Qu, Chunxu, Shi, Lei, Pounds, Stanley, Willman, Cheryl L., Harvey, Richard, Racevskis, Janis, Barinka, Jan, Zhang, Yanming, Dewald, Gordon W., Ketterling, Rhett P., Alejos, David, Lazarus, Hillard M., Luger, Selina M., Foroni, Letizia, Patel, Bela, Fielding, Adele K., Melnick, Ari, Marks, David I., Moorman, Anthony V., Wiernik, Peter H., Rowe, Jacob M., Tallman, Martin S., Goldstone, Anthony H., Mullighan, Charles G., and Litzow, Mark R.

Published
2021
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22. Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.

Author

Chang, Ti-Cheng, Chen, Wenan, Qu, Chunxu, Cheng, Zhongshan, Hedges, Dale, Elsayed, Abdelrahman, Pounds, Stanley B., Shago, Mary, Rabin, Karen R., Raetz, Elizabeth A., Devidas, Meenakshi, Cheng, Cheng, Angiolillo, Anne, Baviskar, Pradyuamna, Borowitz, Michael, Burke, Michael J., Carroll, Andrew, Carroll, William L., Chen, I-Ming, and Harvey, Richard

Published
2024
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23. Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study

Author

Karol, Seth E, Alexander, Thomas B, Budhraja, Amit, Pounds, Stanley B, Canavera, Kristin, Wang, Lei, Wolf, Joshua, Klco, Jeffery M, Mead, Paul E, Das Gupta, Soumyasri, Kim, Su Y, Salem, Ahmed Hamed, Palenski, Tammy, Lacayo, Norman J, Pui, Ching-Hon, Opferman, Joseph T, and Rubnitz, Jeffrey E

Published
2020
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24. Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma

Author

Leventaki, Vasiliki, primary, Shaw, Timothy, additional, Pounds, Stanley, additional, Cao, Xueyuan, additional, Ma, Jing, additional, Palacios, Gustavo, additional, Mason, John, additional, Perkins, Sherrie, additional, Wu, Gang, additional, Fan, Yiping, additional, Wang, Jian, additional, Zhou, Xin, additional, Obermayer, Alyssa, additional, Kinney, Marsha, additional, Kraveka, Jacqueline, additional, Gross, Thomas, additional, Sandlund, John, additional, Zhang, Jinghui, additional, Mullighan, Charles, additional, and Lim, Megan, additional

Published
2024
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26. Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia

Author

Gocho, Yoshihiro, Liu, Jingjing, Hu, Jianzhong, Yang, Wentao, Dharia, Neekesh V., Zhang, Jingliao, Shi, Hao, Du, Guoqing, John, August, Lin, Ting-Nien, Hunt, Jeremy, Huang, Xin, Ju, Bensheng, Rowland, Lauren, Shi, Lei, Maxwell, Dylan, Smart, Brandon, Crews, Kristine R., Yang, Wenjian, Hagiwara, Kohei, Zhang, Yingchi, Roberts, Kathryn, Wang, Hong, Jabbour, Elias, Stock, Wendy, Eisfelder, Bartholomew, Paietta, Elisabeth, Newman, Scott, Roti, Giovanni, Litzow, Mark, Easton, John, Zhang, Jinghui, Peng, Junmin, Chi, Hongbo, Pounds, Stanley, Relling, Mary V., Inaba, Hiroto, Zhu, Xiaofan, Kornblau, Steven, Pui, Ching-Hon, Konopleva, Marina, Teachey, David, Mullighan, Charles G., Stegmaier, Kimberly, Evans, William E., Yu, Jiyang, and Yang, Jun J.

Published
2021
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27. 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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28. Pharmacogenomics of intracellular methotrexate polyglutamates in patients' leukemia cells in vivo

Author

Lopez-Lopez, Elixabet, Autry, Robert J., Smith, Colton, Yang, Wenjian, Paugh, Steven W., Panetta, John C., Crews, Kristine R., Bonten, Erik J., Smart, Brandon, Pei, Deqing, McCorkle, J. Robert, Diouf, Barthelemy, Roberts, Kathryn G., Shi, Lei, Pounds, Stanley, Cheng, Cheng, Mullighan, Charles G., Pui, Ching-Hon, Relling, Mary V., and Evans, William E.

Subjects
Care and treatment, Development and progression, Research, Patient outcomes, Methotrexate -- Patient outcomes, Pharmacological research, Leukemia -- Development and progression -- Care and treatment, Pharmacogenomics -- Research
Abstract

Introduction Acute lymphoblastic leukemia (ALL) is a common disseminated malignancy that is cured by combination chemotherapy in approximately 90% of children and 70% of adults (1-3). Achieving sufficient concentrations of [...], BACKGROUND. Interpatient differences in the accumulation of methotrexate's active polyglutamylated metabolites (MTXPGs) in leukemia cells influence its antileukemic effects. METHODS. To identify genomic and epigenomic and patient variables determining the intracellular accumulation of MTXPGs, we measured intracellular MTXPG levels in acute lymphoblastic leukemia (ALL) cells from 388 newly diagnosed patients after in vivo high-dose methotrexate (HDMTX) (1 g/[m.sup.2]) treatment, defined ALL subtypes, and assessed genomic and epigenomic variants influencing folate pathway genes (mRNA, miRNA, copy number alterations [CNAs], SNPs, single nucleotide variants [SNVs], CpG methylation). RESULTS. We documented greater than 100-fold differences in MTXPG levels, which influenced its antileukemic effects (P = 4 * [10.sup.-5]). Three ALL subtypes had lower MTXPG levels (T cell ALL [T-ALL] and B cell ALL [B-ALL] with the TCF3-PBX1 or ETV6-RUNX1 fusions), and 2 subtypes had higher MTXPG levels (hyperdiploid and BCR-ABL like). The folate pathway genes SLC19A1, ABCC1, ABCC4, FPGS, and MTHFD1 significantly influenced intracellular MTXPG levels (P = 2.9 * [10.sup.-3] to 3.7 * [10.sup.-8]). A multivariable model including the ALL subtype (P = 1.1 * [10.sup.-14]), the SLC19A1/(ABCC1 + ABCC4) transporter ratio (P = 3.6 * [10.sup.-4]), the MTX infusion time (P = 1.5 * [10.sup.-3]), FPGS mRNA expression (P = 2.1 * [10.sup.-3]), and MTX systemic clearance (P = 4.4 * [10.sup.-2]) explained 42% of the variation in MTXPG accumulation (P = 1.1 * [10.sup.-38]). Model simulations indicated that a longer infusion time (24 h vs. 4 h) was superior in achieving higher intracellular MTXPG levels across all subtypes if ALL. CONCLUSIONS. These findings provide insights into mechanisms underlying interpatient differences in intracellular accumulation of MTXPG in leukemia cells and its antileukemic effects FUNDING. THE National Cancer Institute (NCI) and the Institute of General Medical Sciences of the NIH, the Basque Government Programa Posdoctoral de Perfeccionamiento de Personal Investigador doctor, and the American Lebanese Syrian Associated Charities (ALSAC).

Published
2020
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30. Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia

Author

Autry, Robert J., Paugh, Steven W., Carter, Robert, Shi, Lei, Liu, Jingjing, Ferguson, Daniel C., Lau, Calvin E., Bonten, Erik J., Yang, Wenjian, McCorkle, J. Robert, Beard, Jordan A., Panetta, John C., Diedrich, Jonathan D., Crews, Kristine R., Pei, Deqing, Coke, Christopher J., Natarajan, Sivaraman, Khatamian, Alireza, Karol, Seth E., Lopez-Lopez, Elixabet, Diouf, Barthelemy, Smith, Colton, Gocho, Yoshihiro, Hagiwara, Kohei, Roberts, Kathryn G., Pounds, Stanley, Kornblau, Steven M., Stock, Wendy, Paietta, Elisabeth M., Litzow, Mark R., Inaba, Hiroto, Mullighan, Charles G., Jeha, Sima, Pui, Ching-Hon, Cheng, Cheng, Savic, Daniel, Yu, Jiyang, Gawad, Charles, Relling, Mary V., Yang, Jun J., and Evans, William E.

Published
2020
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32. The acquisition of molecular drivers in pediatric therapy-related myeloid neoplasms

Author

Schwartz, Jason R., Ma, Jing, Kamens, Jennifer, Westover, Tamara, Walsh, Michael P., Brady, Samuel W., Robert Michael, J., Chen, Xiaolong, Montefiori, Lindsey, Song, Guangchun, Wu, Gang, Wu, Huiyun, Branstetter, Cristyn, Hiltenbrand, Ryan, Walsh, Michael F., Nichols, Kim E., Maciaszek, Jamie L., Liu, Yanling, Kumar, Priyadarshini, Easton, John, Newman, Scott, Rubnitz, Jeffrey E., Mullighan, Charles G., Pounds, Stanley, Zhang, Jinghui, Gruber, Tanja, Ma, Xiaotu, and Klco, Jeffery M.

Published
2021
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33. Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice

Author

Abdelhamed, Sherif, Thomas, Melvin E., III, Westover, Tamara, Umeda, Masayuki, Xiong, Emily, Rolle, Chandra, Walsh, Michael P., Wu, Huiyun, Schwartz, Jason R., Valentine, Virginia, Valentine, Marcus, Pounds, Stanley, Ma, Jing, Janke, Laura J., and Klco, Jeffery M.

Subjects
Physiological aspects, Development and progression, Genetic aspects, Health aspects, Pediatric research, Bone marrow -- Physiological aspects -- Genetic aspects, Hematopoiesis -- Health aspects -- Genetic aspects, Gene mutation -- Physiological aspects -- Health aspects, Myelodysplastic syndromes -- Genetic aspects -- Development and progression, Acute myelocytic leukemia -- Genetic aspects -- Development and progression, Gene mutations -- Physiological aspects -- Health aspects
Abstract

Introduction Pediatric myelodysplastic syndromes (MDSs) are characterized by impaired hematopoiesis, peripheral blood (PB) cytopenias, hypocellular bone marrows (BMs), and frequent deletions involving chromosome 7 (chr7) (1) and are associated with [...], SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have impaired hematopoiesis, hypocellular marrows, and a greater risk of developing clonal chromosome 7 deletions leading to MDS and AML. We recently demonstrated that expressing SAMD9 or SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces cell death. Here, we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. Using a range of in vivo and ex vivo assays, we showed that cells with heterozygous Samd9l mutations have impaired stemness relative to wild-type counterparts, which was exacerbated by inflammatory stimuli, and ultimately led to bone marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-[beta] as a potential targetable pathway. Further, we observed nonrandom genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking chromosome 7 deletions observed in patients. Collectively, our study has enhanced our understanding of mutant Samd9l hematopoietic phenotypes, emphasized the synergistic role of inflammation in exaggerating the associated hematopoietic defects, and provided insights into potential therapeutic options for patients.

Published
2022
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36. AML-158 Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation

Author

Michmerhuizen, Nicole, Chandra, Bappaditya, Shirnekhi, Hazheen, Tripathi, Swarnendu, Pioso, Brittany, Baggett, David, Mitrea, Diana, lacobucci, Ilaria, White, Michael, Chen, Jingjing, Park, Cheon-Gil, Wu, Huiyun, Pounds, Stanley, Medyukhina, Anna, Khairy, Khaled, Gao, Qingsong, Qu, Chunxu, Gorman, Scott, Bawa, Simran, Maslanka, Carolyn, Kinger, Swati, Dogra, Priyanka, Giacomo, Danika Di, Mecucci, Cristina, Klco, Jeffery, Mullighan, Charles, and Kriwacki, Richard

Published
2022
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39. Cross-species genomic and epigenomic landscape of retinoblastoma

Author

Benavente, Claudia A, McEvoy, Justina D, Finkelstein, David, Wei, Lei, Kang, Guolian, Wang, Yong-Dong, Neale, Geoffrey, Ragsdale, Susan, Valentine, Virginia, Bahrami, Armita, Temirov, Jamshid, Pounds, Stanley, Zhang, Jinghui, and Dyer, Michael A

Subjects
Rare Diseases, Genetics, Cancer, Pediatric, Pediatric Research Initiative, Human Genome, Eye Disease and Disorders of Vision, Pediatric Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Disease Models, Animal, Epigenomics, Gene Expression Regulation, Neoplastic, Genetic Engineering, Genomics, Humans, Mice, Mice, Knockout, Retinoblastoma, Retinoblastoma Protein, Species Specificity, retinoblastoma, RB1, epigenetics, Oncology and Carcinogenesis
Abstract

Genetically engineered mouse models (GEMMs) of human cancer are important for advancing our understanding of tumor initiation and progression as well as for testing novel therapeutics. Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. GEMMs faithfully recapitulate the histopathology, molecular, cellular, morphometric, neuroanatomical and neurochemical features of human retinoblastoma. In this study, we analyzed the genomic and epigenomic landscape of murine retinoblastoma and compared them to human retinoblastomas to gain insight into shared mechanisms of tumor progression across species. Similar to human retinoblastoma, mouse tumors have low rates of single nucleotide variations. However, mouse retinoblastomas have higher rates of aneuploidy and regional and focal copy number changes that vary depending on the genetic lesions that initiate tumorigenesis in the developing murine retina. Furthermore, the epigenetic landscape in mouse retinoblastoma was significantly different from human tumors and some pathways that are candidates for molecular targeted therapy for human retinoblastoma such as SYK or MCL1 are not deregulated in GEMMs. Taken together, these data suggest there are important differences between mouse and human retinoblastomas with respect to the mechanism of tumor progression and those differences can have significant implications for translational research to test the efficacy of novel therapies for this devastating childhood cancer.

Published
2013

40. H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo

Author

Silveira, André B., Kasper, Lawryn H., Fan, Yiping, Jin, Hongjian, Wu, Gang, Shaw, Timothy I., Zhu, Xiaoyan, Larson, Jon D., Easton, John, Shao, Ying, Yergeau, Donald A., Rosencrance, Celeste, Boggs, Kristy, Rusch, Michael C., Ding, Liang, Zhang, Junyuan, Finkelstein, David, Noyes, Rachel M., Russell, Brent L., Xu, Beisi, Broniscer, Alberto, Wetmore, Cynthia, Pounds, Stanley B., Ellison, David W., Zhang, Jinghui, and Baker, Suzanne J.

Published
2019
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41. A novel retinoblastoma therapy from genomic and epigenetic analyses.

Author

Zhang, Jinghui, Benavente, Claudia A, McEvoy, Justina, Flores-Otero, Jacqueline, Ding, Li, Chen, Xiang, Ulyanov, Anatoly, Wu, Gang, Wilson, Matthew, Wang, Jianmin, Brennan, Rachel, Rusch, Michael, Manning, Amity L, Ma, Jing, Easton, John, Shurtleff, Sheila, Mullighan, Charles, Pounds, Stanley, Mukatira, Suraj, Gupta, Pankaj, Neale, Geoff, Zhao, David, Lu, Charles, Fulton, Robert S, Fulton, Lucinda L, Hong, Xin, Dooling, David J, Ochoa, Kerri, Naeve, Clayton, Dyson, Nicholas J, Mardis, Elaine R, Bahrami, Armita, Ellison, David, Wilson, Richard K, Downing, James R, and Dyer, Michael A

Subjects
Cell Line, Animals, Humans, Mice, Retinoblastoma, Aneuploidy, Chromosomal Instability, Intracellular Signaling Peptides and Proteins, Retinoblastoma Protein, Protein Kinase Inhibitors, Xenograft Model Antitumor Assays, Sequence Analysis, DNA, Genomics, Cell Death, Cell Survival, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Mutation, Genes, Retinoblastoma, Protein-Tyrosine Kinases, Molecular Targeted Therapy, Syk Kinase, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Genes, Sequence Analysis, DNA, General Science & Technology
Abstract

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.

Published
2012

42. Identification and targeting of treatment resistant progenitor populations in T-cell Acute Lymphoblastic Leukemia

Author

Tan, Kai, primary, Xu, Jason, additional, Chen, Changya, additional, Vincent, Tiffaney, additional, Pölönen, Petri, additional, Hu, Jianzhong, additional, Yoshimura, Satoshi, additional, Yu, Wenbao, additional, Sussman, Jonathan, additional, Chen, Chia-hui, additional, Li, Elizabeth, additional, Diorio, Caroline, additional, Shraim, Rawan, additional, Newman, Haley, additional, Uppuluri, Lahari, additional, Li, Alexander, additional, Chen, Gregory, additional, Bandyopadhyay, Shovik, additional, Wu, David, additional, Ding, Yang-yang, additional, Xu, Jessica, additional, Lim, Tristan, additional, Hsu, Miles, additional, Thadi, Anusha, additional, Ahn, Kyung Jin, additional, Wu, Chi-Yun, additional, Peng, Jacqueline, additional, Sun, Yusha, additional, Wang, Alice, additional, Mehta, Rushabh, additional, Frank, David, additional, Meyer, Lauren, additional, Loh, Mignon, additional, Raetz, Elizabeth, additional, Chen, Zhiguo, additional, Wood, Brent, additional, Devidas, Meenakshi, additional, Dunsmore, Kimberly, additional, Winter, Stuart, additional, Chang, Ti-Cheng, additional, Wu, Gang, additional, Pounds, Stanley, additional, Zhang, Nancy, additional, Carroll, William, additional, Hunger, Stephen, additional, Bernt, Kathrin, additional, Yang, Jun, additional, Mullighan, Charles, additional, and Teachey, David, additional

Published
2023
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43. The genomic basis of childhood T-lineage acute lymphoblastic leukemia

Author

Mullighan, Charles, primary, Pölönen, Petri, additional, Giacomo, Danika Di, additional, Seffernick, Anna, additional, Elsayed, Abdelrahman, additional, Kimura, Shunsuke, additional, Benini, Francesca, additional, Montefiori, Lindsey, additional, Wood, Brent, additional, Xu, Jason, additional, Chen, Changya, additional, Cheng, Zhongshan, additional, Newman, Haley, additional, Myers, Jason, additional, Iacobucci, Ilaria, additional, Li, Elizabeth, additional, Sussman, Jonathan, additional, Hedges, Dale, additional, Hui, Yawei, additional, Diorio, Caroline, additional, Uppuluri, Lahari, additional, Frank, David, additional, Fan, Yiping, additional, Chang, Yunchao, additional, Meshinchi, Soheil, additional, Ries, Rhonda, additional, Shraim, Rawan, additional, Li, Alexander, additional, Bernt, Kathrin, additional, Devidas, Meenakshi, additional, Winter, Stuart, additional, Dunsmore, Kimberley, additional, Inaba, Hiroto, additional, Carroll, William, additional, Ramirez, Nilsa, additional, Philips, Aaron, additional, Kriwacki, Richard, additional, Yang, Jun, additional, Vincent, Tiffaney, additional, Loh, Mignon, additional, Rampersaud, Evadnie, additional, Raetz, Elizabeth, additional, Hunger, Stephen, additional, Tan, Kai, additional, Chang, Ti-Cheng, additional, Wu, Gang, additional, Pounds, Stanley, additional, and Teachey, David, additional

Published
2023
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45. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia

Author

Gu, Zhaohui, Churchman, Michelle L., Roberts, Kathryn G., Moore, Ian, Zhou, Xin, Nakitandwe, Joy, Hagiwara, Kohei, Pelletier, Stephane, Gingras, Sebastien, Berns, Hartmut, Payne-Turner, Debbie, Hill, Ashley, Iacobucci, Ilaria, Shi, Lei, Pounds, Stanley, Cheng, Cheng, Pei, Deqing, Qu, Chunxu, Newman, Scott, Devidas, Meenakshi, Dai, Yunfeng, Reshmi, Shalini C., Gastier-Foster, Julie, Raetz, Elizabeth A., Borowitz, Michael J., Wood, Brent L., Carroll, William L., Zweidler-McKay, Patrick A., Rabin, Karen R., Mattano, Leonard A., Maloney, Kelly W., Rambaldi, Alessandro, Spinelli, Orietta, Radich, Jerald P., Minden, Mark D., Rowe, Jacob M., Luger, Selina, Litzow, Mark R., Tallman, Martin S., Racevskis, Janis, Zhang, Yanming, Bhatia, Ravi, Kohlschmidt, Jessica, Mrózek, Krzysztof, Bloomfield, Clara D., Stock, Wendy, Kornblau, Steven, Kantarjian, Hagop M., Konopleva, Marina, Evans, Williams E., Jeha, Sima, Pui, Ching-Hon, Yang, Jun, Paietta, Elisabeth, Downing, James R., Relling, Mary V., Zhang, Jinghui, Loh, Mignon L., Hunger, Stephen P., and Mullighan, Charles G.

Published
2019
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46. The genetic basis and cell of origin of mixed phenotype acute leukaemia

Author

Alexander, Thomas B., Gu, Zhaohui, Iacobucci, Ilaria, Dickerson, Kirsten, Choi, John K., Xu, Beisi, Payne-Turner, Debbie, Yoshihara, Hiroki, Loh, Mignon L., Horan, John, Buldini, Barbara, Basso, Giuseppe, Elitzur, Sarah, de Haas, Valerie, Zwaan, C. Michel, Yeoh, Allen, Reinhardt, Dirk, Tomizawa, Daisuke, Kiyokawa, Nobutaka, Lammens, Tim, De Moerloose, Barbara, Catchpoole, Daniel, Hori, Hiroki, Moorman, Anthony, Moore, Andrew S., Hrusak, Ondrej, Meshinchi, Soheil, Orgel, Etan, Devidas, Meenakshi, Borowitz, Michael, Wood, Brent, Heerema, Nyla A., Carrol, Andrew, Yang, Yung-Li, Smith, Malcolm A., Davidsen, Tanja M., Hermida, Leandro C., Gesuwan, Patee, Marra, Marco A., Ma, Yussanne, Mungall, Andrew J., Moore, Richard A., Jones, Steven J. M., Valentine, Marcus, Janke, Laura J., Rubnitz, Jeffrey E., Pui, Ching-Hon, Ding, Liang, Liu, Yu, Zhang, Jinghui, Nichols, Kim E., Downing, James R., Cao, Xueyuan, Shi, Lei, Pounds, Stanley, Newman, Scott, Pei, Deqing, Guidry Auvil, Jaime M., Gerhard, Daniela S., Hunger, Stephen P., Inaba, Hiroto, and Mullighan, Charles G.

Published
2018
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49. Multi-organ Mapping of Cancer Risk

Author

Zhu, Liqin, Finkelstein, David, Gao, Culian, Shi, Lei, Wang, Yongdong, López-Terrada, Dolores, Wang, Kasper, Utley, Sarah, Pounds, Stanley, Neale, Geoffrey, Ellison, David, Onar-Thomas, Arzu, and Gilbertson, Richard James

Published
2016
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