Research Papers:

CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia

Chiara Palmi, Angela M. Savino, Daniela Silvestri, Ilaria Bronzini, Gunnar Cario, Maddalena Paganin, Barbara Buldini, Marta Galbiati, Martina U. Muckenthaler, Cristina Bugarin, Pamela Della Mina, Stefan Nagel, Elena Barisone, Fiorina Casale, Franco Locatelli, Luca Lo Nigro, Concetta Micalizzi, Rosanna Parasole, Andrea Pession, Maria C. Putti, Nicola Santoro, Anna M. Testi, Ottavio Ziino, Andreas E. Kulozik, Martin Zimmermann, Martin Schrappe, Antonello Villa, Giuseppe Gaipa, Giuseppe Basso, Andrea Biondi, Maria G. Valsecchi, Martin Stanulla, Valentino Conter, Geertruy te Kronnie and Giovanni Cazzaniga _

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Oncotarget. 2016; 7:59260-59272. https://doi.org/10.18632/oncotarget.10610

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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

Correspondence to:

Giovanni Cazzaniga, email: [email protected]

Andrea Biondi, email: [email protected]

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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