title: CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Palmi
authors.affiliation: Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Savino
authors.affiliation: Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Milan, Italy.|Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Silvestri
authors.affiliation: Laboratory of Onco-Hematology, Department SDB, Università di Padova, Padova, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bronzini
authors.affiliation: Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.affiliation: Laboratory of Onco-Hematology, Department SDB, Università di Padova, Padova, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Paganin
authors.affiliation: Laboratory of Onco-Hematology, Department SDB, Università di Padova, Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Buldini
authors.affiliation: Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Galbiati
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and EMBL/Medical Faculty Molecular Medicine Partnership Unit, Heidelberg, Germany.
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.affiliation: Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bugarin
authors.affiliation: Microscopy and Image Analysis Consortium, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Della Mina
authors.affiliation: Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nagel
authors.affiliation: Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Barisone
authors.affiliation: Pediatric Oncology Service, Pediatric Department of 2nd University of Naples, Naples, Italy.
authors.forename: Fiorina
authors.initials: F
authors.lastname: Casale
authors.affiliation: Department of Pediatric Hematology/Oncology, IRCCS Ospedale Bambino Gesù, Rome - University of Pavia, Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Center of Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria "Policlinico Vittorio Emanuele", Catania, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Lo Nigro
authors.affiliation: Hematology/Oncology Unit, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Micalizzi
authors.affiliation: Department of Pediatric Hemato-Oncology, Ospedale Pausilipon, Napoli, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Parasole
authors.affiliation: Department of Pediatrics, "Lalla Seràgnoli" Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pession
authors.affiliation: Laboratory of Onco-Hematology, Department SDB, Università di Padova, Padova, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Putti
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology-Oncology, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Santoro
authors.affiliation: Division of Hematology, Department of Biotechnologies and Hematology, "Sapienza" University of Rome, Rome, Italy.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Testi
authors.affiliation: Pediatric Hematology and Oncology Unit, A.R.N.A.S. Civico, Di Cristina and Benfratelli Hospital, Palermo, Italy.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Ziino
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and EMBL/Medical Faculty Molecular Medicine Partnership Unit, Heidelberg, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.affiliation: Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Microscopy and Image Analysis Consortium, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Villa
authors.affiliation: Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gaipa
authors.affiliation: Laboratory of Onco-Hematology, Department SDB, Università di Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Valsecchi
authors.affiliation: Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Valentino
authors.initials: V
authors.lastname: Conter
authors.affiliation: Laboratory of Onco-Hematology, Department SDB, Università di Padova, Padova, Italy.
authors.forename: Geertruy
authors.initials: G
authors.lastname: Te Kronnie
authors.affiliation: Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C498762:CRLF2 protein, human; D018121:Receptors, Cytokine
keywords: CRLF2; T acute lymphoblastic leukemia; high risk; pediatric leukemia; prognostic marker