title: CRLF2 overexpression identifies an unfavourable subgroup of adult B-cell precursor acute lymphoblastic leukemia lacking recurrent genetic abnormalities.
abstract: BACKGROUND
  A deregulated CRLF2 (d-CRLF2) expression was described in B-cell acute lymphoblastic leukemia without recurrent fusion genes (B-NEG ALL). While the role of d-CRLF2 in children has been extensively described, little is known about its role and impact in adult ALL.
  
  
  METHODS
  Expression levels of CRLF2 were evaluated by quantitative real-time PCR in 102 newly-diagnosed adult B-NEG ALL and correlated with the clinico-biological characteristics and outcome. Incidence and clinical impact of the P2RY8/CRLF2 transcript was also assessed.
  
  
  RESULTS
  High CRLF2 levels, as continuous variable, were significantly associated with hyperleucocytosis (p=0.0002) and thrombocytopenia (p=0.005); when a cut-point at ΔCt≤8 was applied, 35 cases (34.3%), mostly males (80%), proved positive for CRLF2 expression. High CRLF2 levels, as continuous or categorical variable, were associated with a worse disease-free (p=0.003 and p=0.015) and overall survival (p=0.017 and 0.0038). Furthermore, when CRLF2 was analyzed as a categorical variable, a high statistical association was found with IKZF1 deletion and mutations in the JAK/STAT pathway (p=0.001 and p<0.0001, respectively). Finally, the P2RY8/CRLF2 transcript, identified in 8/102 patients (7.8%), was associated with a poor outcome.
  
  
  CONCLUSIONS
  In adult B-NEG ALL, high CRLF2 expression is associated with distinct clinico-biological features and an unfavourable prognosis in both univariate and multivariate analysis; similarly, P2RY8/CRLF2 positivity correlates with a poor outcome. The quantification of CRLF2 is an important prognostic marker in adult B-lineage ALL without known genetic lesions.
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Brugnoletti
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.affiliation: GIMEMA Data Center, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Paoloni
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Fedullo
authors.affiliation: GIMEMA Data Center, Rome, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Piciocchi
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Elia
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Vitale
authors.affiliation: Division of Hematology, AOU Policlinico-OVE, University of Catania, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Mauro
authors.affiliation: Division of Hematology and Stem Cell Transplantation Unit, Cardarelli Hospital, Naples, Italy.
authors.forename: Felicetto
authors.initials: F
authors.lastname: Ferrara
authors.affiliation: Hematology, Sant'Eugenio Hospital, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: De Fabritiis
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Luppi
authors.affiliation: Hematology Unit, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ronco
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors.forename: Maria Stefania
authors.initials: MS
authors.lastname: De Propris
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Raponi
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Italy.
authors.forename: Geertruy Te
authors.initials: GT
authors.lastname: Kronnie
authors.affiliation: GIMEMA Data Center, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Vignetti
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome, Italy. Electronic address: rfoa@bce.uniroma1.it.
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction; D018121:Receptors, Cytokine / Q000096:biosynthesis* / Q000235:genetics; D058470:Receptors, Purinergic P2Y / Q000235:genetics; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C498762:CRLF2 protein, human; C578279:P2RY8 protein, human; D018121:Receptors, Cytokine; D058470:Receptors, Purinergic P2Y
keywords: Acute lymphoblastic leukemia; Adult patients; CRLF2 overexpression; Prognosis