Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αβ lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% ( = .177).
Klingler-Hoffmann Manuela, Fodero-Tavoletti Michelle T., Mishima Kazuhiko, Narita Yoshitaka, Cavenee Webster K., Furnari Frank B., Huang H.-J. Su, Tiganis Tony, The Protein Tyrosine Phosphatase TCPTP Suppresses the Tumorigenicity of Glioblastoma Cells Expressing a Mutant Epidermal Growth Factor Receptor, 10.1074/jbc.m106571200
Marks D. I., Paietta E. M., Moorman A. V., Richards S. M., Buck G., DeWald G., Ferrando A., Fielding A. K., Goldstone A. H., Ketterling R. P., Litzow M. R., Luger S. M., McMillan A. K., Mansour M. R., Rowe J. M., Tallman M. S., Lazarus H. M., T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993), 10.1182/blood-2009-08-231217
Persson C., Savenhed C., Bourdeau A., Tremblay M. L., Markova B., Bohmer F. D., Haj F. G., Neel B. G., Elson A., Heldin C.-H., Ronnstrand L., Ostman A., Hellberg C., Site-Selective Regulation of Platelet-Derived Growth Factor Receptor Tyrosine Phosphorylation by T-Cell Protein Tyrosine Phosphatase, 10.1128/mcb.24.5.2190-2201.2004
Sangwan Veena, Paliouras Grigorios N., Abella Jasmine V., Dubé Nadia, Monast Anie, Tremblay Michel L., Park Morag, Regulation of the Met Receptor-tyrosine Kinase by the Protein-tyrosine Phosphatase 1B and T-cell Phosphatase, 10.1074/jbc.m805916200
Wiede Florian, Shields Benjamin J., Chew Sock Hui, Kyparissoudis Konstantinos, van Vliet Catherine, Galic Sandra, Tremblay Michel L., Russell Sarah M., Godfrey Dale I., Tiganis Tony, T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice, 10.1172/jci59492
Shields Ben J., Hauser Christine, Bukczynska Patricia E., Court Naomi W., Tiganis Tony, DNA Replication Stalling Attenuates Tyrosine Kinase Signaling to Suppress S Phase Progression, 10.1016/j.ccr.2008.06.003
ten Hoeve J., de Jesus Ibarra-Sanchez M., Fu Y., Zhu W., Tremblay M., David M., Shuai K., Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase, 10.1128/mcb.22.16.5662-5668.2002
Yamamoto Tetsuya, Sekine Yuichi, Kashima Keiichi, Kubota Atsuko, Sato Noriko, Aoki Naohito, Matsuda Tadashi, The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation, 10.1016/s0006-291x(02)02291-x
Lu Xiaoqing, Chen Jun, Sasmono R. Tedjo, Hsi Eric D., Sarosiek Kristopher A., Tiganis Tony, Lossos Izidore S., T-Cell Protein Tyrosine Phosphatase, Distinctively Expressed in Activated-B-Cell-Like Diffuse Large B-Cell Lymphomas, Is the Nuclear Phosphatase of STAT6, 10.1128/mcb.01234-06
Kleppe M., Tousseyn T., Geissinger E., Kalender Atak Z., Aerts S., Rosenwald A., Wlodarska I., Cools J., Mutation analysis of the tyrosine phosphatase PTPN2 in Hodgkin's lymphoma and T-cell non-Hodgkin's lymphoma, 10.3324/haematol.2011.041921
Pike Kelly A., Tremblay Michel L., TC-PTP and PTP1B: Regulating JAK–STAT signaling, controlling lymphoid malignancies, 10.1016/j.cyto.2015.12.025
Hunger Stephen P., Mullighan Charles G., Acute Lymphoblastic Leukemia in Children, 10.1056/nejmra1400972
Bergeron J., Clappier E., Radford I., Buzyn A., Millien C., Soler G., Ballerini P., Thomas X., Soulier J., Dombret H., Macintyre E. A., Asnafi V., Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs, 10.1182/blood-2007-04-079988
van Dongen J J M, , Lhermitte L, Böttcher S, Almeida J, van der Velden V H J, Flores-Montero J, Rawstron A, Asnafi V, Lécrevisse Q, Lucio P, Mejstrikova E, Szczepański T, Kalina T, de Tute R, Brüggemann M, Sedek L, Cullen M, Langerak A W, Mendonça A, Macintyre E, Martin-Ayuso M, Hrusak O, Vidriales M B, Orfao A, EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes, 10.1038/leu.2012.120
Trinquand Amélie, Tanguy-Schmidt Aline, Ben Abdelali Raouf, Lambert Jérôme, Beldjord Kheira, Lengliné Etienne, De Gunzburg Noémie, Payet-Bornet Dominique, Lhermitte Ludovic, Mossafa Hossein, Lhéritier Véronique, Bond Jonathan, Huguet Françoise, Buzyn Agnès, Leguay Thibaud, Cahn Jean-Yves, Thomas Xavier, Chalandon Yves, Delannoy André, Bonmati Caroline, Maury Sebastien, Nadel Bertrand, Macintyre Elizabeth, Ifrah Norbert, Dombret Hervé, Asnafi Vahid, Toward a NOTCH1/FBXW7/RAS/PTEN–Based Oncogenetic Risk Classification of Adult T-Cell Acute Lymphoblastic Leukemia: A Group for Research in Adult Acute Lymphoblastic Leukemia Study, 10.1200/jco.2012.48.5292
Vicente C., Schwab C., Broux M., Geerdens E., Degryse S., Demeyer S., Lahortiga I., Elliott A., Chilton L., La Starza R., Mecucci C., Vandenberghe P., Goulden N., Vora A., Moorman A. V., Soulier J., Harrison C. J., Clappier E., Cools J., Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia, 10.3324/haematol.2015.130179
Bond Jonathan, Graux Carlos, Lhermitte Ludovic, Lara Diane, Cluzeau Thomas, Leguay Thibaut, Cieslak Agata, Trinquand Amélie, Pastoret Cedric, Belhocine Mohamed, Spicuglia Salvatore, Lheritier Véronique, Leprêtre Stéphane, Thomas Xavier, Huguet Françoise, Ifrah Norbert, Dombret Hervé, Macintyre Elizabeth, Boissel Nicolas, Asnafi Vahid, Early Response–Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study, 10.1200/jco.2016.71.8585
Hanahan Douglas, Weinberg Robert A., Hallmarks of Cancer: The Next Generation, 10.1016/j.cell.2011.02.013
Durieux Anne-Cécile, Prudhon Bernard, Guicheney Pascale, Bitoun Marc, Dynamin 2 and human diseases, 10.1007/s00109-009-0587-4
Tremblay C S, Brown F C, Collett M, Saw J, Chiu S K, Sonderegger S E, Lucas S E, Alserihi R, Chau N, Toribio M L, McCormack M P, Chircop M, Robinson P J, Jane S M, Curtis D J, Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling, 10.1038/leu.2016.100
Van Vlierberghe Pieter, Palomero Teresa, Khiabanian Hossein, Van der Meulen Joni, Castillo Mireia, Van Roy Nadine, De Moerloose Barbara, Philippé Jan, González-García Sara, Toribio María L, Taghon Tom, Zuurbier Linda, Cauwelier Barbara, Harrison Christine J, Schwab Claire, Pisecker Markus, Strehl Sabine, Langerak Anton W, Gecz Jozef, Sonneveld Edwin, Pieters Rob, Paietta Elisabeth, Rowe Jacob M, Wiernik Peter H, Benoit Yves, Soulier Jean, Poppe Bruce, Yao Xiaopan, Cordon-Cardo Carlos, Meijerink Jules, Rabadan Raul, Speleman Frank, Ferrando Adolfo, PHF6 mutations in T-cell acute lymphoblastic leukemia, 10.1038/ng.542
Wiede Florian, Dudakov Jarrod A., Lu Kun-Hui, Dodd Garron T., Butt Tariq, Godfrey Dale I., Strasser Andreas, Boyd Richard L., Tiganis Tony, PTPN2 regulates T cell lineage commitment and αβ versus γδ specification, 10.1084/jem.20161903
Ferrando Adolfo A., Neuberg Donna S., Staunton Jane, Loh Mignon L., Huard Christine, Raimondi Susana C., Behm Fred G., Pui Ching-Hon, Downing James R., Gilliland D.Gary, Lander Eric S., Golub Todd R., Look A.Thomas, Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia, 10.1016/s1535-6108(02)00018-1
Tesio M, Trinquand A, Macintyre E, Asnafi V, Oncogenic PTEN functions and models in T-cell malignancies, 10.1038/onc.2015.462
Tesio M, Trinquand A, Ballerini P, Hypolite G, Lhermitte L, Petit A, Ifrah N, Baruchel A, Dombret H, Macintyre E, Asnafi V, Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia, 10.1038/leu.2017.157
Bornschein S, Demeyer S, Stirparo R, Gielen O, Vicente C, Geerdens E, Ghesquière B, Aerts S, Cools J, de Bock C E, Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system, 10.1038/leu.2017.328
Pongers-Willemse MJ, Verhagen OJHM, Tibbe GJM, Wijkhuijs AJM, de Haas V, Roovers E, van der Schoot CE, van Dongen JJM, Real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia using junctional region specific TaqMan probes, 10.1038/sj.leu.2401246
van der Velden V H J, , Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grumayer E R, Flohr T, Sutton R, Cave H, Madsen H O, Cayuela J M, Trka J, Eckert C, Foroni L, zur Stadt U, Beldjord K, Raff T, van der Schoot C E, van Dongen J J M, Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data, 10.1038/sj.leu.2404586
Asnafi V., Analysis of TCR, pTalpha , and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment, 10.1182/blood-2002-08-2438
Soulier J., HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL), 10.1182/blood-2004-10-3900
Van Vlierberghe Pieter, Ferrando Adolfo, The molecular basis of T cell acute lymphoblastic leukemia, 10.1172/jci61269
Kleppe Maria, Lahortiga Idoya, El Chaar Tiama, De Keersmaecker Kim, Mentens Nicole, Graux Carlos, Van Roosbroeck Katrien, Ferrando Adolfo A, Langerak Anton W, Meijerink Jules P P, Sigaux François, Haferlach Torsten, Wlodarska Iwona, Vandenberghe Peter, Soulier Jean, Cools Jan, Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia, 10.1038/ng.587
Kleppe M., Soulier J., Asnafi V., Mentens N., Hornakova T., Knoops L., Constantinescu S., Sigaux F., Meijerink J. P., Vandenberghe P., Tartaglia M., Foa R., Macintyre E., Haferlach T., Cools J., PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia, 10.1182/blood-2010-10-314286
Liu Yu, Easton John, Shao Ying, Maciaszek Jamie, Wang Zhaoming, Wilkinson Mark R, McCastlain Kelly, Edmonson Michael, Pounds Stanley B, Shi Lei, Zhou Xin, Ma Xiaotu, Sioson Edgar, Li Yongjin, Rusch Michael, Gupta Pankaj, Pei Deqing, Cheng Cheng, Smith Malcolm A, Auvil Jaime Guidry, Gerhard Daniela S, Relling Mary V, Winick Naomi J, Carroll Andrew J, Heerema Nyla A, Raetz Elizabeth, Devidas Meenakshi, Willman Cheryl L, Harvey Richard C, Carroll William L, Dunsmore Kimberly P, Winter Stuart S, Wood Brent L, Sorrentino Brian P, Downing James R, Loh Mignon L, Hunger Stephen P, Zhang Jinghui, Mullighan Charles G, The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia, 10.1038/ng.3909
Bibliographic reference
Alcantara, Marion ; Simonin, Mathieu ; Lhermitte, Ludovic ; Touzart, Aurore ; Dourthe, Marie Emilie ; et. al. Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia.. In: Blood advances, Vol. 3, no. 13, p. 1981-1988 (2019)
