CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia
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Chiara Palmi1, Angela M. Savino1, Daniela Silvestri2,3, Ilaria Bronzini4, Gunnar Cario5, Maddalena Paganin4, Barbara Buldini4, Marta Galbiati1, Martina U. Muckenthaler6, Cristina Bugarin1, Pamela Della Mina7, Stefan Nagel8, Elena Barisone9, Fiorina Casale10, Franco Locatelli11, Luca Lo Nigro12, Concetta Micalizzi13, Rosanna Parasole14, Andrea Pession15, Maria C. Putti4, Nicola Santoro16, Anna M. Testi17, Ottavio Ziino18, Andreas E. Kulozik6, Martin Zimmermann19, Martin Schrappe5, Antonello Villa7, Giuseppe Gaipa1, Giuseppe Basso4, Andrea Biondi3, Maria G. Valsecchi2, Martin Stanulla19, Valentino Conter3, Geertruy te Kronnie4, Giovanni Cazzaniga1
1Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy
2Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Milan, Italy
3Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy
4Laboratory of Onco-Hematology, Department SDB, Università di Padova, Padova, Italy
5Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
6Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and EMBL/Medical Faculty Molecular Medicine Partnership Unit, Heidelberg, Germany
7Microscopy and Image Analysis Consortium, Università di Milano-Bicocca, Monza, Italy
8Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
9Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children’s Hospital, Turin, Italy
10Pediatric Oncology Service, Pediatric Department of 2nd University of Naples, Naples, Italy
11Department of Pediatric Hematology/Oncology, IRCCS Ospedale Bambino Gesù, Rome - University of Pavia, Pavia, Italy
12Center of Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria “Policlinico Vittorio Emanuele”, Catania, Italy
13Hematology/Oncology Unit, G. Gaslini Children’s Hospital, Genoa, Italy
14Department of Pediatric Hemato-Oncology, Ospedale Pausilipon, Napoli, Italy
15Department of Pediatrics, “Lalla Seràgnoli” Hematology-Oncology Unit, University of Bologna, Bologna, Italy
16Department of Pediatrics, Division of Pediatric Hematology-Oncology, University “A. Moro” of Bari, Bari, Italy
17Division of Hematology, Department of Biotechnologies and Hematology, “Sapienza” University of Rome, Rome, Italy
18Pediatric Hematology and Oncology Unit, A.R.N.A.S. Civico, Di Cristina and Benfratelli Hospital, Palermo, Italy
19Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany
Giovanni Cazzaniga, email: firstname.lastname@example.org
Andrea Biondi, email: email@example.com
Keywords: CRLF2, pediatric leukemia, T acute lymphoblastic leukemia, prognostic marker, high risk
Received: May 20, 2016 Accepted: July 01, 2016 Published: July 15, 2016
Pediatric T-ALL patients have a worse outcome compared to BCP-ALL patients and they could benefit from new prognostic marker identification. Alteration of CRLF2 gene, a hallmark correlated with poor outcome in BCP-ALL, has not been reported in T-ALL.
We analyzed CRLF2 expression in 212 T-ALL pediatric patients enrolled in AIEOP-BFM ALL2000 study in Italian and German centers.
Seventeen out of 120 (14.2%) Italian patients presented CRLF2 mRNA expression 5 times higher than the median (CRLF2-high); they had a significantly inferior event-free survival (41.2%±11.9 vs. 68.9%±4.6, p=0.006) and overall survival (47.1%±12.1 vs. 73.8%±4.3, p=0.009) and an increased cumulative incidence of relapse/resistance (52.9%±12.1 vs. 26.2%±4.3, p=0.007) compared to CRLF2-low patients. The prognostic value of CRLF2 over-expression was validated in the German cohort. Of note, CRLF2 over-expression was associated with poor prognosis in the high risk (HR) subgroup where CRLF2-high patients were more frequently allocated.
Interestingly, although in T-ALL CRLF2 protein was localized mainly in the cytoplasm, in CRLF2-high blasts we found a trend towards a stronger TSLP-induced pSTAT5 response, sensitive to the JAK inhibitor Ruxolitinib.
In conclusion, CRLF2 over-expression is a poor prognostic marker identifying a subset of HR T-ALL patients that could benefit from alternative therapy, potentially targeting the CRLF2 pathway.
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