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1. Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma.

Author

Ocasio-Martinez, Nicole, Tsai, Harrison, Li, Yuting, Robichaud, Amanda, Khalid, Delan, Hatton, Charlie, Gillani, Riaz, Polonen, Petri, Dilig, Anthony, Gotti, Giacomo, Kavanagh, Julia, Adhav, Asmani, Gow, Sean, Tsai, Jonathan, Li, Yen, Ebert, Benjamin, Van Allen, Eliezer, Bledsoe, Jacob, Kim, Annette, Tasian, Sarah, Cooper, Stacy, Cooper, Todd, Hijiya, Nobuko, Sulis, Maria, Shukla, Neerav, Magee, Jeffrey, Mullighan, Charles, Burke, Michael, Luskin, Marlise, Mar, Brenton, Harris, Marian, Stegmaier, Kimberly, Place, Andrew, Pikman, Yana, Paolino, Jonathan, Dimitrov, Boris, Apsel Winger, Beth, Sandoval-Perez, Angelica, Jacobson, Matthew, and Rangarajan, Amith

Subjects
Humans, Child, Animals, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Platelet-Derived Growth Factor alpha, Mutation, Receptor Protein-Tyrosine Kinases, Precursor Cell Lymphoblastic Leukemia-Lymphoma, T-Lymphocytes
Abstract

PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy. EXPERIMENTAL DESIGN: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia. RESULTS: Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL. CONCLUSIONS: Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.

Published
2023

2. Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia

Author

Ryan, Sarra L., Peden, John F., Kingsbury, Zoya, Schwab, Claire J., James, Terena, Polonen, Petri, Mijuskovic, Martina, Becq, Jenn, Yim, Richard, Cranston, Ruth E., Hedges, Dale J., Roberts, Kathryn G., Mullighan, Charles G., Vora, Ajay, Russell, Lisa J., Bain, Robert, Moorman, Anthony V., Bentley, David R., Harrison, Christine J., and Ross, Mark T.

Published
2023
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3. Coronary Artery Disease Risk Variant Dampens the Expression of CALCRL by Reducing HSF Binding to Shear Stress Responsive Enhancer in Endothelial Cells In Vitro

Author

Selvarajan, Ilakya, Kiema, Miika, Huang, Ru-Ting, Li, Jin, Zhu, Jiayu, Polonen, Petri, Ord, Tiit, Ounap, Kadri, Godiwala, Mehvash, Golebiewski, Anna Kathryn, Ravindran, Aarthi, Maeklin, Kiira, Toropainen, Anu, Stolze, Lindsey K., Arce, Maximiliano, Magnusson, Peetra, White, Stephen, Romanoski, Casey E., Heinaniemi, Merja, Laakkonen, Johanna P., Fang, Yun, Kaikkonen, Minna U., Selvarajan, Ilakya, Kiema, Miika, Huang, Ru-Ting, Li, Jin, Zhu, Jiayu, Polonen, Petri, Ord, Tiit, Ounap, Kadri, Godiwala, Mehvash, Golebiewski, Anna Kathryn, Ravindran, Aarthi, Maeklin, Kiira, Toropainen, Anu, Stolze, Lindsey K., Arce, Maximiliano, Magnusson, Peetra, White, Stephen, Romanoski, Casey E., Heinaniemi, Merja, Laakkonen, Johanna P., Fang, Yun, and Kaikkonen, Minna U.

Abstract

BACKGROUND:CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of CALCRL expression in endothelial cells.METHODS:To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene CALCRL, we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells.RESULTS:We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of CALCRL expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and CALCRL expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. CALCRL knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a

Published
2024
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4. Data from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Author

Paolino, Jonathan, primary, Dimitrov, Boris, primary, Apsel Winger, Beth, primary, Sandoval-Perez, Angelica, primary, Rangarajan, Amith Vikram, primary, Ocasio-Martinez, Nicole, primary, Tsai, Harrison K., primary, Li, Yuting, primary, Robichaud, Amanda L., primary, Khalid, Delan, primary, Hatton, Charlie, primary, Gillani, Riaz, primary, Polonen, Petri, primary, Dilig, Anthony, primary, Gotti, Giacomo, primary, Kavanagh, Julia, primary, Adhav, Asmani A., primary, Gow, Sean, primary, Tsai, Jonathan, primary, Li, Yen Der, primary, Ebert, Benjamin L., primary, Van Allen, Eliezer M., primary, Bledsoe, Jacob, primary, Kim, Annette S., primary, Tasian, Sarah K., primary, Cooper, Stacy L., primary, Cooper, Todd M., primary, Hijiya, Nobuko, primary, Sulis, Maria Luisa, primary, Shukla, Neerav N., primary, Magee, Jeffrey A., primary, Mullighan, Charles G., primary, Burke, Michael J., primary, Luskin, Marlise R., primary, Mar, Brenton G., primary, Jacobson, Matthew P., primary, Harris, Marian H., primary, Stegmaier, Kimberly, primary, Place, Andrew E., primary, and Pikman, Yana, primary

Published
2023
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5. Supplementary Table 4 from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Author

Paolino, Jonathan, primary, Dimitrov, Boris, primary, Apsel Winger, Beth, primary, Sandoval-Perez, Angelica, primary, Rangarajan, Amith Vikram, primary, Ocasio-Martinez, Nicole, primary, Tsai, Harrison K., primary, Li, Yuting, primary, Robichaud, Amanda L., primary, Khalid, Delan, primary, Hatton, Charlie, primary, Gillani, Riaz, primary, Polonen, Petri, primary, Dilig, Anthony, primary, Gotti, Giacomo, primary, Kavanagh, Julia, primary, Adhav, Asmani A., primary, Gow, Sean, primary, Tsai, Jonathan, primary, Li, Yen Der, primary, Ebert, Benjamin L., primary, Van Allen, Eliezer M., primary, Bledsoe, Jacob, primary, Kim, Annette S., primary, Tasian, Sarah K., primary, Cooper, Stacy L., primary, Cooper, Todd M., primary, Hijiya, Nobuko, primary, Sulis, Maria Luisa, primary, Shukla, Neerav N., primary, Magee, Jeffrey A., primary, Mullighan, Charles G., primary, Burke, Michael J., primary, Luskin, Marlise R., primary, Mar, Brenton G., primary, Jacobson, Matthew P., primary, Harris, Marian H., primary, Stegmaier, Kimberly, primary, Place, Andrew E., primary, and Pikman, Yana, primary

Published
2023
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6. Supplementary Figure 2 from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Author

Paolino, Jonathan, primary, Dimitrov, Boris, primary, Apsel Winger, Beth, primary, Sandoval-Perez, Angelica, primary, Rangarajan, Amith Vikram, primary, Ocasio-Martinez, Nicole, primary, Tsai, Harrison K., primary, Li, Yuting, primary, Robichaud, Amanda L., primary, Khalid, Delan, primary, Hatton, Charlie, primary, Gillani, Riaz, primary, Polonen, Petri, primary, Dilig, Anthony, primary, Gotti, Giacomo, primary, Kavanagh, Julia, primary, Adhav, Asmani A., primary, Gow, Sean, primary, Tsai, Jonathan, primary, Li, Yen Der, primary, Ebert, Benjamin L., primary, Van Allen, Eliezer M., primary, Bledsoe, Jacob, primary, Kim, Annette S., primary, Tasian, Sarah K., primary, Cooper, Stacy L., primary, Cooper, Todd M., primary, Hijiya, Nobuko, primary, Sulis, Maria Luisa, primary, Shukla, Neerav N., primary, Magee, Jeffrey A., primary, Mullighan, Charles G., primary, Burke, Michael J., primary, Luskin, Marlise R., primary, Mar, Brenton G., primary, Jacobson, Matthew P., primary, Harris, Marian H., primary, Stegmaier, Kimberly, primary, Place, Andrew E., primary, and Pikman, Yana, primary

Published
2023
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7. Supplementary Table 3 from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Author

Paolino, Jonathan, primary, Dimitrov, Boris, primary, Apsel Winger, Beth, primary, Sandoval-Perez, Angelica, primary, Rangarajan, Amith Vikram, primary, Ocasio-Martinez, Nicole, primary, Tsai, Harrison K., primary, Li, Yuting, primary, Robichaud, Amanda L., primary, Khalid, Delan, primary, Hatton, Charlie, primary, Gillani, Riaz, primary, Polonen, Petri, primary, Dilig, Anthony, primary, Gotti, Giacomo, primary, Kavanagh, Julia, primary, Adhav, Asmani A., primary, Gow, Sean, primary, Tsai, Jonathan, primary, Li, Yen Der, primary, Ebert, Benjamin L., primary, Van Allen, Eliezer M., primary, Bledsoe, Jacob, primary, Kim, Annette S., primary, Tasian, Sarah K., primary, Cooper, Stacy L., primary, Cooper, Todd M., primary, Hijiya, Nobuko, primary, Sulis, Maria Luisa, primary, Shukla, Neerav N., primary, Magee, Jeffrey A., primary, Mullighan, Charles G., primary, Burke, Michael J., primary, Luskin, Marlise R., primary, Mar, Brenton G., primary, Jacobson, Matthew P., primary, Harris, Marian H., primary, Stegmaier, Kimberly, primary, Place, Andrew E., primary, and Pikman, Yana, primary

Published
2023
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8. Supplementary Table 1 from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Author

Paolino, Jonathan, primary, Dimitrov, Boris, primary, Apsel Winger, Beth, primary, Sandoval-Perez, Angelica, primary, Rangarajan, Amith Vikram, primary, Ocasio-Martinez, Nicole, primary, Tsai, Harrison K., primary, Li, Yuting, primary, Robichaud, Amanda L., primary, Khalid, Delan, primary, Hatton, Charlie, primary, Gillani, Riaz, primary, Polonen, Petri, primary, Dilig, Anthony, primary, Gotti, Giacomo, primary, Kavanagh, Julia, primary, Adhav, Asmani A., primary, Gow, Sean, primary, Tsai, Jonathan, primary, Li, Yen Der, primary, Ebert, Benjamin L., primary, Van Allen, Eliezer M., primary, Bledsoe, Jacob, primary, Kim, Annette S., primary, Tasian, Sarah K., primary, Cooper, Stacy L., primary, Cooper, Todd M., primary, Hijiya, Nobuko, primary, Sulis, Maria Luisa, primary, Shukla, Neerav N., primary, Magee, Jeffrey A., primary, Mullighan, Charles G., primary, Burke, Michael J., primary, Luskin, Marlise R., primary, Mar, Brenton G., primary, Jacobson, Matthew P., primary, Harris, Marian H., primary, Stegmaier, Kimberly, primary, Place, Andrew E., primary, and Pikman, Yana, primary

Published
2023
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9. Supplementary Table 5 from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Author

Paolino, Jonathan, primary, Dimitrov, Boris, primary, Apsel Winger, Beth, primary, Sandoval-Perez, Angelica, primary, Rangarajan, Amith Vikram, primary, Ocasio-Martinez, Nicole, primary, Tsai, Harrison K., primary, Li, Yuting, primary, Robichaud, Amanda L., primary, Khalid, Delan, primary, Hatton, Charlie, primary, Gillani, Riaz, primary, Polonen, Petri, primary, Dilig, Anthony, primary, Gotti, Giacomo, primary, Kavanagh, Julia, primary, Adhav, Asmani A., primary, Gow, Sean, primary, Tsai, Jonathan, primary, Li, Yen Der, primary, Ebert, Benjamin L., primary, Van Allen, Eliezer M., primary, Bledsoe, Jacob, primary, Kim, Annette S., primary, Tasian, Sarah K., primary, Cooper, Stacy L., primary, Cooper, Todd M., primary, Hijiya, Nobuko, primary, Sulis, Maria Luisa, primary, Shukla, Neerav N., primary, Magee, Jeffrey A., primary, Mullighan, Charles G., primary, Burke, Michael J., primary, Luskin, Marlise R., primary, Mar, Brenton G., primary, Jacobson, Matthew P., primary, Harris, Marian H., primary, Stegmaier, Kimberly, primary, Place, Andrew E., primary, and Pikman, Yana, primary

Published
2023
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10. Supplementary Table 6 from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Author

Paolino, Jonathan, primary, Dimitrov, Boris, primary, Apsel Winger, Beth, primary, Sandoval-Perez, Angelica, primary, Rangarajan, Amith Vikram, primary, Ocasio-Martinez, Nicole, primary, Tsai, Harrison K., primary, Li, Yuting, primary, Robichaud, Amanda L., primary, Khalid, Delan, primary, Hatton, Charlie, primary, Gillani, Riaz, primary, Polonen, Petri, primary, Dilig, Anthony, primary, Gotti, Giacomo, primary, Kavanagh, Julia, primary, Adhav, Asmani A., primary, Gow, Sean, primary, Tsai, Jonathan, primary, Li, Yen Der, primary, Ebert, Benjamin L., primary, Van Allen, Eliezer M., primary, Bledsoe, Jacob, primary, Kim, Annette S., primary, Tasian, Sarah K., primary, Cooper, Stacy L., primary, Cooper, Todd M., primary, Hijiya, Nobuko, primary, Sulis, Maria Luisa, primary, Shukla, Neerav N., primary, Magee, Jeffrey A., primary, Mullighan, Charles G., primary, Burke, Michael J., primary, Luskin, Marlise R., primary, Mar, Brenton G., primary, Jacobson, Matthew P., primary, Harris, Marian H., primary, Stegmaier, Kimberly, primary, Place, Andrew E., primary, and Pikman, Yana, primary

Published
2023
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11. Supplementary Table 2 from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Author

Paolino, Jonathan, primary, Dimitrov, Boris, primary, Apsel Winger, Beth, primary, Sandoval-Perez, Angelica, primary, Rangarajan, Amith Vikram, primary, Ocasio-Martinez, Nicole, primary, Tsai, Harrison K., primary, Li, Yuting, primary, Robichaud, Amanda L., primary, Khalid, Delan, primary, Hatton, Charlie, primary, Gillani, Riaz, primary, Polonen, Petri, primary, Dilig, Anthony, primary, Gotti, Giacomo, primary, Kavanagh, Julia, primary, Adhav, Asmani A., primary, Gow, Sean, primary, Tsai, Jonathan, primary, Li, Yen Der, primary, Ebert, Benjamin L., primary, Van Allen, Eliezer M., primary, Bledsoe, Jacob, primary, Kim, Annette S., primary, Tasian, Sarah K., primary, Cooper, Stacy L., primary, Cooper, Todd M., primary, Hijiya, Nobuko, primary, Sulis, Maria Luisa, primary, Shukla, Neerav N., primary, Magee, Jeffrey A., primary, Mullighan, Charles G., primary, Burke, Michael J., primary, Luskin, Marlise R., primary, Mar, Brenton G., primary, Jacobson, Matthew P., primary, Harris, Marian H., primary, Stegmaier, Kimberly, primary, Place, Andrew E., primary, and Pikman, Yana, primary

Published
2023
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12. Supplementary Figure 1 from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

Author

Paolino, Jonathan, primary, Dimitrov, Boris, primary, Apsel Winger, Beth, primary, Sandoval-Perez, Angelica, primary, Rangarajan, Amith Vikram, primary, Ocasio-Martinez, Nicole, primary, Tsai, Harrison K., primary, Li, Yuting, primary, Robichaud, Amanda L., primary, Khalid, Delan, primary, Hatton, Charlie, primary, Gillani, Riaz, primary, Polonen, Petri, primary, Dilig, Anthony, primary, Gotti, Giacomo, primary, Kavanagh, Julia, primary, Adhav, Asmani A., primary, Gow, Sean, primary, Tsai, Jonathan, primary, Li, Yen Der, primary, Ebert, Benjamin L., primary, Van Allen, Eliezer M., primary, Bledsoe, Jacob, primary, Kim, Annette S., primary, Tasian, Sarah K., primary, Cooper, Stacy L., primary, Cooper, Todd M., primary, Hijiya, Nobuko, primary, Sulis, Maria Luisa, primary, Shukla, Neerav N., primary, Magee, Jeffrey A., primary, Mullighan, Charles G., primary, Burke, Michael J., primary, Luskin, Marlise R., primary, Mar, Brenton G., primary, Jacobson, Matthew P., primary, Harris, Marian H., primary, Stegmaier, Kimberly, primary, Place, Andrew E., primary, and Pikman, Yana, primary

Published
2023
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13. Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young

Author

Kimura, Shunsuke, primary, Polonen, Petri, additional, Montefiori, Lindsey, additional, Park, Chun Shik, additional, Iacobucci, Ilaria, additional, Yeoh, Allen EJ, additional, Attarbaschi, Andishe, additional, Moore, Andrew S., additional, Brown, Anthony, additional, Manabe, Atsushi, additional, Buldini, Barbara, additional, Freeman, Burgess B., additional, Chen, Chelsey, additional, Cheng, Cheng, additional, Kean Hui, Chiew, additional, Li, Chi-Kong, additional, Pui, Ching-Hon, additional, Qu, Chunxu, additional, Tomizawa, Daisuke, additional, Teachey, David T., additional, Varotto, Elena, additional, M Paietta, Elisabeth, additional, Arnold, Elizabeth D., additional, Locatelli, Franco, additional, Escherich, Gabriele, additional, Elisa Muhle, Hannah, additional, Marquart, Hanne Vibeke, additional, de Groot-Kruseman, Hester A., additional, Rowe, Jacob M, additional, Stary, Jan, additional, Trka, Jan, additional, Choi, John Kim, additional, Meijerink, Jules P.P., additional, Yang, Jun J., additional, Takita, Junko, additional, Pawinska-Wasikowska, Katarzyna, additional, Roberts, Kathryn G., additional, Han, Katie, additional, Caldwell, Kenneth J., additional, Schmiegelow, Kjeld, additional, Crews, Kristine R., additional, Eguchi, Mariko, additional, Schrappe, Martin, additional, Zimmerman, Martin, additional, Takagi, Masatoshi, additional, Maybury, Mellissa, additional, Svaton, Michael, additional, Reiterova, Michaela, additional, Kicinski, Michal, additional, Prater, Mollie S., additional, Kato, Motohiro, additional, Reyes, Noemi, additional, Spinelli, Orietta, additional, Thomas, Paul, additional, Mazilier, Pauline, additional, Gao, Qingsong, additional, Masetti, Riccardo, additional, Kotecha, Rishi S, additional, Pieters, Rob, additional, Elitzur, Sarah, additional, Luger, Selina M., additional, Mitchell, Sharnise, additional, Pruett-Miller, Shondra M., additional, Shen, Shuhong, additional, Jeha, Sima, additional, Kohrer, Stefan, additional, Kornblau, Steven M, additional, Skoczen, Szymon, additional, Miyamura, Takako, additional, Vincent, Tiffaney L, additional, Imamura, Toshihiko, additional, Conter, Valentino, additional, Tang, Yanjing, additional, Liu, Yen-Chun, additional, Chang, Yunchao, additional, Gu, Zhaohui, additional, Cheng, Zhongshan, additional, Yinmei, Zhou, additional, Inaba, Hiroto, additional, and Mullighan, Charles G., additional

Published
2023
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14. Integration of genomic sequencing drives therapeutic targeting of PDGFRA in T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma.

Author

Paolino, Jonathan, primary, Dimitrov, Boris, additional, Apsel Winger, Beth, additional, Sandoval-Perez, Angelica, additional, Rangarajan, Amith Vikram., additional, Ocasio-Martinez, Nicole, additional, Tsai, Harrison K., additional, Li, Yuting, additional, Robichaud, Amanda L., additional, Khalid, Delan, additional, Hatton, Charlie, additional, Gillani, Riaz, additional, Polonen, Petri, additional, Dilig, Anthony, additional, Gotti, Giacomo, additional, Kavanagh, Julia, additional, Adhav, Asmani A., additional, Gow, Sean, additional, Tsai, Jonathan, additional, Li, Yen Der, additional, Ebert, Benjamin L., additional, Van Allen, Eliezer M., additional, Bledsoe, Jacob, additional, Kim, Annette S., additional, Tasian, Sarah K., additional, Cooper, Stacy L., additional, Cooper, Todd M., additional, Hijiya, Nobuko, additional, Sulis, Maria Luisa, additional, Shukla, Neerav N., additional, Magee, Jeffrey A., additional, Mullighan, Charles G., additional, Burke, Michael J., additional, Luskin, Marlise R., additional, Mar, Brenton G., additional, Jacobson, Matthew P., additional, Harris, Marian H., additional, Stegmaier, Kimberly, additional, Place, Andrew E., additional, and Pikman, Yana, additional

Published
2023
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15. Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia

Author

Ryan, Sarra, primary, Peden, John, additional, Kingsbury, Zoya, additional, Schwab, Claire, additional, James, Terena, additional, Polonen, Petri, additional, Mijuskovic, Martina, additional, Becq, Jennifer, additional, Yim, Richard, additional, Cranston, Ruth, additional, Hedges, Dale, additional, Roberts, Kathryn, additional, Mullighan, Charles, additional, Vora, Ajay, additional, Russell, Lisa, additional, Moorman, Anthony, additional, Bentley, David, additional, Harrison, Christine, additional, and Ross, Mark, additional

Published
2022
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16. A TARGETED GENE EXPRESSION CLASSIFIER IDENTIFIES PEDIATRIC T-ALL PATIENTS AT HIGH RISK FOR END INDUCTION MINIMAL RESIDUAL DISEASE POSITIVITY

Author

Meyer, L., primary, Roy, Ritu P., additional, Huang, B., additional, Kimura, S., additional, Polonen, Petri, additional, Delgado-Martin, C., additional, Vincent, T., additional, Ryan, T., additional, Wood, B., additional, Liu, Y., additional, Zhang, J., additional, Mullighan, C., additional, Horton, T., additional, Loh, M., additional, Devidas, M., additional, Raetz, E., additional, Hayashi, R., additional, Winter, S., additional, Dunsmore, K., additional, Hunger, S., additional, Teachey, D., additional, Hermiston, M., additional, and Olshen, Adam B., additional

Published
2022
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17. ALL-144: Oncogenic Deregulation of BCL11B in Lineage Ambiguous Leukemia

Author

Montefiori, Lindsey E., primary, Bendig, Sonja, additional, Gu, Zhaohui, additional, Chen, Xiaolong, additional, Polonen, Petri, additional, Ma, Xiaotu, additional, Murison, Alex, additional, Zeng, Andy, additional, Garcia-Prat, Laura, additional, Dickerson, Kirsten, additional, Iacobucci, Ilaria, additional, Abdelhamed, Sherif, additional, Hiltenbrand, Ryan, additional, Mead, Paul E., additional, Mehr, Cyrus M., additional, Xu, Beisi, additional, Cheng, Zhongshan, additional, Chang, Ti-Cheng, additional, Westover, Tamara, additional, Ma, Jing, additional, Stengel, Anna, additional, Kimura, Shunsuke, additional, Qu, Chunxu, additional, Valentine, Marcus B., additional, Rashkovan, Marissa, additional, Luger, Selina, additional, Litzow, Mark R., additional, Rowe, Jacob M., additional, den Boer, Monique L., additional, Wang, Victoria, additional, Yin, Jun, additional, Kornblau, Steven M., additional, Hunger, Stephen P., additional, Loh, Mignon L., additional, Pui, Ching-Hon, additional, Yang, Wenjian, additional, Crews, Kristine R., additional, Roberts, Kathryn G., additional, Yang, Jun J., additional, Relling, Mary V., additional, Evans, William E., additional, Stock, Wendy, additional, Paietta, Elisabeth M., additional, Ferrando, Adolfo A., additional, Zhang, Jinghui, additional, Kern, Wolfgang, additional, Haferlach, Torsten, additional, Wu, Gang, additional, Dick, John E., additional, Klco, Jeffery M., additional, Haferlach, Claudia, additional, and Mullighan, Charles G., additional

Published
2021
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18. Poster: ALL-144: Oncogenic Deregulation of BCL11B in Lineage Ambiguous Leukemia

Author

Montefiori, Lindsey E., primary, Bendig, Sonja, additional, Gu, Zhaohui, additional, Chen, Xiaolong, additional, Polonen, Petri, additional, Ma, Xiaotu, additional, Murison, Alex, additional, Zeng, Andy, additional, Garcia-Prat, Laura, additional, Dickerson, Kirsten, additional, Iacobucci, Ilaria, additional, Abdelhamed, Sherif, additional, Hiltenbrand, Ryan, additional, Mead, Paul E., additional, Mehr, Cyrus M., additional, Xu, Beisi, additional, Cheng, Zhongshan, additional, Chang, Ti-Cheng, additional, Westover, Tamara, additional, Ma, Jing, additional, Stengel, Anna, additional, Kimura, Shunsuke, additional, Qu, Chunxu, additional, Valentine, Marcus B., additional, Rashkovan, Marissa, additional, Luger, Selina, additional, Litzow, Mark R., additional, Rowe, Jacob M., additional, den Boer, Monique L., additional, Wang, Victoria, additional, Yin, Jun, additional, Kornblau, Steven M., additional, Hunger, Stephen P., additional, Loh, Mignon L., additional, Pui, Ching-Hon, additional, Yang, Wenjian, additional, Crews, Kristine R., additional, Roberts, Kathryn G., additional, Yang, Jun J., additional, Relling, Mary V., additional, Evans, William E., additional, Stock, Wendy, additional, Paietta, Elisabeth M., additional, Ferrando, Adolfo A., additional, Zhang, Jinghui, additional, Kern, Wolfgang, additional, Haferlach, Torsten, additional, Wu, Gang, additional, Dick, John E., additional, Klco, Jeffery M., additional, Haferlach, Claudia, additional, and Mullighan, Charles G., additional

Published
2021
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20. Oncogenic Deregulation of BCL11B in Lineage Ambiguous Leukemia

Author

Montefiori, Lindsey E., Bendig, Sonja, Gu, Zhaohui, Chen, Xiaolong, Polonen, Petri, Ma, Xiaotu, Murison, Alex, Zeng, Andy, Garcia-Prat, Laura, Dickerson, Kirsten, Iacobucci, Ilaria, Abdelhamed, Sherif, Hiltenbrand, Ryan, Mead, Paul E., Mehr, Cyrus M., Beisi Xu, Cheng, Zhongshan, Chang, Ti-Cheng, Westover, Tamara, Ma, Jing, Stengel, Anna, Kimura, Shunsuke, Qu, Chunxu, Valentine, Marcus B., Rashkovan, Marissa, Luger, Selina, Litzow, Mark R., Rowe, Jacob M., Den Boer, Monique L., Wang, Victoria, Yin, Jun, Kornblau, Steven M., Hunger, Stephen P., Loh, Mignon L., Pui, Ching-Hon, Yang, Wenjian, Crews, Kristine R., Roberts, Kathryn G., Yang, Jun J., Relling, Mary V., Evans, William E., Stock, Wendy, Paietta, Elisabeth M., Ferrando, Adolfo A., Zhang, Jinghui, Kern, Wolfgang, Haferlach, Torsten, Wu, Gang, Dick, John E., Klco, Jeffery M., Haferlach, Claudia, and Mullighan, Charles G.

21. Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

Author

Kimura S, Polonen P, Montefiori L, Park CS, Iacobucci I, Yeoh AE, Attarbaschi A, Moore AS, Brown A, Manabe A, Buldini B, Freeman BB, Chen C, Cheng C, Kean Hui C, Li CK, Pui CH, Qu C, Tomizawa D, Teachey DT, Varotto E, Paietta EM, Arnold ED, Locatelli F, Escherich G, Elisa Muhle H, Marquart HV, de Groot-Kruseman HA, Rowe JM, Stary J, Trka J, Choi JK, Meijerink JPP, Yang JJ, Takita J, Pawinska-Wasikowska K, Roberts KG, Han K, Caldwell KJ, Schmiegelow K, Crews KR, Eguchi M, Schrappe M, Zimmerman M, Takagi M, Maybury M, Svaton M, Reiterova M, Kicinski M, Prater MS, Kato M, Reyes N, Spinelli O, Thomas P, Mazilier P, Gao Q, Masetti R, Kotecha RS, Pieters R, Elitzur S, Luger SM, Mitchell S, Pruett-Miller SM, Shen S, Jeha S, Köhrer S, Kornblau SM, Skoczeń S, Miyamura T, Vincent TL, Imamura T, Conter V, Tang Y, Liu YC, Chang Y, Gu Z, Cheng Z, Yinmei Z, Inaba H, and Mullighan CG

Abstract

Purpose: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease., Methods: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts., Results: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], P =9.5 x 10 -5 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], P =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating LMO2 activation and inactivating STAG2 inactivation ( STAG2/LMO2 ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine., Conclusion: γδ T-ALL in children under the age of three is extremely high-risk and enriched for STAG2/LMO2 ALL. STAG2 loss perturbs chromatin conformation and differentiation, and STAG2/LMO2 ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL., Support: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173., Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.

Published
2023
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