CRLF2 overexpression identifies an unfavourable subgroup of adult B-cell precursor acute lymphoblastic leukemia lacking recurrent genetic abnormalities

被引:41
作者
Chiaretti, Sabina [1 ]
Brugnoletti, Fulvia [1 ]
Messina, Monica [1 ]
Paoloni, Francesca [2 ]
Fedullo, Anna Lucia [1 ]
Piciocchi, Alfonso [2 ]
Elia, Loredana [1 ]
Vitale, Antonella [1 ]
Mauro, Elisa [3 ]
Ferrara, Felicetto [4 ,5 ]
De Fabritiis, Paolo [6 ]
Luppi, Mario [7 ]
Ronco, Francesca [8 ]
De Propris, Maria Stefania [1 ]
Raponi, Sara [1 ]
te Kronnie, Geertruy [9 ]
Vignetti, Marco [2 ]
Guarini, Anna [1 ]
Foa, Robin [1 ]
机构
[1] Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, Hematol, Rome, Italy
[2] GIMEMA Data Ctr, Rome, Italy
[3] Univ Catania, Div Hematol, AOU Policlin OVE, I-95124 Catania, Italy
[4] Cardarelli Hosp, Div Hematol, Naples, Italy
[5] Cardarelli Hosp, Stem Cell Transplantat Unit, Naples, Italy
[6] St Eugenio Hosp, Hematol, Rome, Italy
[7] Univ Modena & Reggio Emilia, Dept Med & Surg Sci, Div Hematol, Modena, Italy
[8] Azienda Osped Bianchi Melacrino Morelli, Hematol Unit, Reggio Di Calabria, Italy
[9] Univ Padua, Lab Oncohematol, Dept Womens & Childrens Hlth, I-35100 Padua, Italy
关键词
CRLF2; overexpression; Acute lymphoblastic leukemia; Adult patients; Prognosis; MINIMAL RESIDUAL DISEASE; CD66C EXPRESSION; IKZF1; DELETIONS; POOR-PROGNOSIS; CHILDREN; REARRANGEMENT; CLASSIFICATION; PROGENITOR; KINASE; JAK;
D O I
10.1016/j.leukres.2015.11.018
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 Delta Ct <= 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 IKZFI 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. (C) 2015 Elsevier Ltd. All rights reserved.
引用
收藏
页码:36 / 42
页数:7
相关论文
共 38 条
[1]   Modern Therapy of Acute Lymphoblastic Leukemia [J].
Bassan, Renato ;
Hoelzer, Dieter .
JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (05) :532-543
[2]   Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations [J].
Buitenkamp, T. D. ;
Pieters, R. ;
Gallimore, N. E. ;
van der Veer, A. ;
Meijerink, J. P. P. ;
Beverloo, H. B. ;
Zimmermann, M. ;
de Haas, V. ;
Richards, S. M. ;
Vora, A. J. ;
Mitchell, C. D. ;
Russell, L. J. ;
Schwab, C. ;
Harrison, C. J. ;
Moorman, A. V. ;
van den Heuvel-Eibrink, M. M. ;
den Boer, M. L. ;
Zwaan, C. M. .
LEUKEMIA, 2012, 26 (10) :2204-2211
[3]   Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol [J].
Cario, Gunnar ;
Zimmermann, Martin ;
Romey, Renja ;
Gesk, Stefan ;
Vater, Inga ;
Harbott, Jochen ;
Schrauder, Andre ;
Moericke, Anja ;
Izraeli, Shai ;
Akasaka, Takashi ;
Dyer, Martin J. S. ;
Siebert, Reiner ;
Schrappe, Martin ;
Stanulla, Martin .
BLOOD, 2010, 115 (26) :5393-5397
[4]   Outcome modeling with CRLF2, IKZF1, JAK and minimal residual disease Study in pediatric acute lymphoblastic leukemia: a Children's Oncology Group [J].
Chen, I. Ming ;
Harvey, Richard C. ;
Mullighan, Charles G. ;
Gastier-Foster, Julie ;
Wharton, Walker ;
Kang, Huining ;
Borowitz, Michael J. ;
Camitta, Bruce M. ;
Carroll, Andrew J. ;
Devidas, Meenakshi ;
Pullen, D. Jeanette ;
Payne-Turner, Debbie ;
Taisan, Sarah K. ;
Reshmi, Shalini ;
Cottrell, Catherine E. ;
Reaman, Gregory H. ;
Bowman, W. Paul ;
Carroll, William L. ;
Loh, Mignon L. ;
Winick, Naomi J. ;
Hunger, Stephen P. ;
Willman, Cheryl L. .
BLOOD, 2012, 119 (15) :3512-3522
[5]   Clinico-biological features of 5202 patients with acute lymphoblastic leukemia enrolled in the Italian AIEOP and GIMEMA protocols and stratified in age cohorts [J].
Chiaretti, Sabina ;
Vitale, Antonella ;
Cazzaniga, Gianni ;
Orlando, Sonia Maria ;
Silvestri, Daniela ;
Fazi, Paola ;
Valsecchi, Maria Grazia ;
Elia, Loredana ;
Testi, Anna Maria ;
Mancini, Francesca ;
Conter, Valentino ;
Kronnie, Geertruy te ;
Ferrara, Felicetto ;
Di Raimondo, Francesco ;
Tedeschi, Alessandra ;
Fioritoni, Giuseppe ;
Fabbiano, Francesco ;
Meloni, Giovanna ;
Specchia, Giorgina ;
Pizzolo, Giovanni ;
Mandelli, Franco ;
Guarini, Anna ;
Basso, Giuseppe ;
Biondi, Andrea ;
Foa, Robin .
HAEMATOLOGICA, 2013, 98 (11) :1702-1710
[6]   A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study [J].
Den Boer, Monique L. ;
van Slegtenhorst, Marjon ;
De Menezes, Renee X. ;
Cheok, Meyling H. ;
Buijs-Gladdines, Jessica G. C. A. M. ;
Peters, Susan T. C. J. M. ;
Van Zutven, Laura C. M. ;
Beverloo, H. Berna ;
Van der Spek, Peter J. ;
Escherich, Gaby ;
Horstmann, Martin A. ;
Janka-Schoub, Gritta E. ;
Kamps, Willem A. ;
Evans, William E. ;
Pieters, Rob .
LANCET ONCOLOGY, 2009, 10 (02) :125-134
[7]   Standardization of Flow Cytometric Minimal Residual Disease Evaluation in Acute Lymphoblastic Leukemia: Multicentric Assessment Is Feasible [J].
Dworzak, Michael Norbert ;
Gaipa, Giuseppe ;
Ratei, Richard ;
Veltroni, Marinella ;
Schumich, Angela ;
Maglia, Oscar ;
Karawajew, Leonid ;
Benetello, Allessandra ;
Poetschger, Ulrike ;
Husak, Zvenyslava ;
Gadner, Helmut ;
Biondi, Andrea ;
Ludwig, Wolf-Dieter ;
Basso, Giuseppe .
CYTOMETRY PART B-CLINICAL CYTOMETRY, 2008, 74B (06) :331-340
[8]  
Elia L, 2003, HAEMATOLOGICA, V88, P275
[9]   Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial [J].
Ensor, Hannah M. ;
Schwab, Claire ;
Russell, Lisa J. ;
Richards, Sue M. ;
Morrison, Heather ;
Masic, Dino ;
Jones, Lisa ;
Kinsey, Sally E. ;
Vora, Ajay J. ;
Mitchell, Christopher D. ;
Harrison, Christine J. ;
Moorman, Anthony V. .
BLOOD, 2011, 117 (07) :2129-2136
[10]   Adult Acute Lymphoblastic Leukemia Concepts and Strategies [J].
Faderl, Stefan ;
O'Brien, Susan ;
Pui, Ching-Hon ;
Stock, Wendy ;
Wetzler, Meir ;
Hoelzer, Dieter ;
Kantarjian, Hagop M. .
CANCER, 2010, 116 (05) :1165-1176