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P2RY8-CRLF2 Fusion but Not for CRLF2 Over-Expression in Children with Intermediate Risk B-Cell Precursor Acute Lymphoblastic Leukemia

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P2RY8-CRLF2 Fusion but Not for CRLF2 Over-Expression in Children with Intermediate Risk B-Cell Precursor Acute Lymphoblastic Leukemia Leukemia (2012) 26, 2245–2253 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu ORIGINAL ARTICLE Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia C Palmi1,9, E Vendramini2,9, D Silvestri3,4, G Longinotti1, D Frison2, G Cario5, C Shochat6,7, M Stanulla5, V Rossi1, AM Di Meglio2, T Villa1, E Giarin2, G Fazio1, A Leszl2, M Schrappe5, G Basso2, A Biondi4, S Izraeli6, V Conter4,8, MG Valsecchi3,9, G Cazzaniga1,9 and G te Kronnie2,9 Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk-adapted therapy largely based on minimal residual disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2) over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (X20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a threefold increase in risk of relapse. Significantly, the cumulative incidence of relapse of the P2RY8-CRLF2 þ patients in the IR group was high (61.1%±12.9 vs 17.6%±2.6, Po0.0001), similar to high-risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification. Leukemia (2012) 26, 2245–2253; doi:10.1038/leu.2012.101 Keywords: CRLF2; pediatric BCP-ALL; prognosis INTRODUCTION (CRLF2)8–13 genes. The latter abnormality includes small The cure rate of new diagnosed pediatric B-cell precursor acute deletions within the pseudoautosomal region (PAR1) of the sex lymphoblastic leukemia (BCP-ALL) is higher than 80%. However, chromosomes as well as the translocation of this region to the the probability of survival of patients who relapse after treatment IGH@ locus on chromosome 14. Several studies have provided is only 30%. In the AIEOP-BFM ALL2000 study, risk group evidence for the mechanistic basis of the over-expression of CRLF2 8,10 stratification was largely based on minimal residual disease as a consequence of these chromosomal abnormalities. PAR1 (MRD) monitoring as a measure of early response to therapy. deletion juxtaposes the first non-coding exon of P2RY8 to the Approximately, 30% of patients were at standard risk (SR), 55% at first exon of CRLF2, leading to CRLF2 expression driven by the intermediate risk (IR) and 15% at high risk (HR) of relapse. In spite promoter of P2RY8. The translocation of PAR1 region to IGH@ of the risk-adapted therapy, the majority of relapses occur in the locus, however, brings CRLF2 under the control of IGH@ enhancer large heterogeneous IR group.1 Therefore, the identification of elements. Elevated CRLF2 expression was found to be associated disease features with prognostic values within current risk groups with IKZF1 deletions and activating JAK2 or CRLF2 point 10–12,14 remains a formidable challenge in childhood ALL. mutations. Chromosomal translocations that were identified as key factors CRLF2 rearrangements were shown to be correlated with poor 12,14 in the pathogenesis of ALL and provided essential prognostic outcome in BCP-ALL patients, but it is still under debate hallmarks have been incorporated in patient risk stratification. whether this prognostic value is associated to CRLF2 over- There is a need to identify which of the recently discovered expression or to specific CRLF2 aberrancies. Moreover, CRLF2 genetic alterations have the potential to improve patient aberrations were not proven to bear significant prognostic value 13 stratification2 as well as for the development of targeted in children with ALL treated on UK protocols. therapeutic approaches.3–5 Here, we present data on the incidence and prognostic impact In a subset of BCP-ALL patients without known chromosomal of CRLF2 over-expression, specifically P2RY8-CRLF2 fusion, at aberrations, two genomic abnormalities have been reported diagnosis in 464 Italian BCP-ALL children treated with the protocol that involve Ikaros (IKZF1)6,7 and cytokine receptor-like factor 2 of the Associazione Italiana Ematologia Oncologia Pediatrica 1Centro Ricerca Tettamanti, Clinica Pediatrica, Universita` di Milano Bicocca, Ospedale San Gerardo, Monza, Italy; 2Laboratory of Oncohematology, Department of Pediatrics, Universita` di Padova, Padova, Italy; 3Centro di Biostatistica per l’Epidemiologia Clinica, Universita` di Milano Bicocca, Monza, Italy; 4Clinica Pediatrica, Universita` di Milano Bicocca, Ospedale San Gerardo, Monza, Italy; 5Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; 6Sheba Medical Center, Tel Hashomer, Ramat Gan and Tel Aviv University, Tel Aviv, Israel; 7Migal-Galilee Bio-Technology Center, Kiryat-Shmona, Israel. and 8Pediatria, Ospedali Riuniti, Bergamo, Italy. Correspondence: Dr G Cazzaniga, Centro Ricerca Tettamanti, Clinica Pediatrica, Universita` di Milano Bicocca, Ospedale San Gerardo, Via Pergolesi, 33, 20900 Monza, Italy. E-mail: [email protected] 9These authors contributed equally to this work. Received 14 October 2011; revised 21 March 2012; accepted 30 March 2012; accepted article preview online 9 April 2012; advance online publication, 11 May 2012 Poor outcome of P2RY8-CRLF2 in childhood ALL C Palmi et al 2246 (AIEOP) and Berlin-Frankfurt-Munster (BFM) group (‘AIEOP-BFM P2RY8-CRLF2 rearrangement was tested in 365 patients at diagnosis ALL2000 protocol’) and the potential impact of P2RY8-CRLF2 and in 26 paired diagnosis and relapse samples for which leftover RNA was fusion within MRD-based subgroups. available. IGH@-CRLF2 translocation was screened in 8 out of 12 patients We also present data on CRLF2 over-expression and P2RY8- who were positive for CRLF2 over-expression (X20 times higher than CRLF2 fusion at BCP-ALL relapse and speculate on P2RY8-CRLF2 overall median) but negative for P2RY8-CRLF2 fusion at diagnosis. DNA was available from 34 patients positive for CRLF2 over-expression or P2RY8- as a secondary event in disease progression. CRLF2 fusion at diagnosis, and the following were analyzed: CRLF2 mutations (in 25 out of 34 patients), JAK2 mutations (in 32 out of 34 patients) and IKZF1 deletions (in 33 out of 34 patients). CRLF2 and JAK2 PATIENTS AND METHODS mutations were also analyzed in 6 and 32 paired diagnosis and relapse Patients samples, respectively. BCP-ALL patients consecutively enrolled in the AIEOP-BFM ALL2000 study The clinical characteristics of the analyzed patients compared with those in AIEOP Centers from February 2003 to July 2005, not affected by Down not analyzed (AIEOP-BFM ALL2000 study patients diagnosed between syndrome (DS) nor Philadelphia chromosome positive (Ph þ ), were September 2000 and July 2006) are shown in Supplementary Table 1, and included in the study cohort. CRLF2 expression was analyzed in 464 their event-free survival (EFS) curve is shown in Supplementary Figure 1a. patients at diagnosis and in 33 paired diagnosis and relapse samples, while Details of the study cohort are shown in the Supplementary Materials. a 1000 100 10 1 expression 0.1 CRLF2 0.01 1 100 200 300 400 Rank (464 pts) CRLF2 expression P2RY8-CRLF2 bc 1000 100 10 100 1 expression expression 10 0.1 CRLF2 CRLF2 1 5 10 15 20 1510 Rank (22 pts) Rank(12 pts) CRLF2 expression IGH@-CRLF2 P2RY8-CRLF2 CRLF2 expression P2RY8-CRLF2 JAK2 mutations JAK2 mutations CRLF2 mutations IKZF1 deletions CRLF2 mutations IKZF1 deletions d Total P2RY8-CRLF2 IGH@-CRLF2 CRLF2 mut JAK2 mut IKZF1 del hiCRLF2 22/464(4.7%) 10/20 1/8 2/22 4/22 5/22 P2RY8-CRLF2 pos 22/365 (6.0%) - - 2/14 4/21 4/21 hiCRLF2 & P2RY8-CRLF2 pos 10/365 (2.7%) - - 2/10 3/10 3/10 hiCRLF2 & P2RY8-CRLF2 neg 10/365 (2.7%) - 1/8 0/10 1/10 1/10 loCRLF2 & P2RY8-CRLF2 pos 12/365 (3.3%) --0/4 1/10 2/11 mut, mutations; del, deletions. Figure 1. CRLF2 expression and genomic alterations. (a) CRLF2 expression in 464 BCP-ALL patients. For each case results are reported as fold changes on the median expression value of all patients in the cohort. Expression ranged from 0.006- to 810-fold change. (b) Additional genomic aberrations in hiCRLF2 patients. In bright blue are cases not tested for P2RY8-CRLF2 fusion. (c) Additional genomic aberrations in loCRLF2 P2RY8-CRLF2-positive patients. (d) Details on the combination of CRLF2 expression, P2RY8-CRLF2 fusion and other genomic aberrations. Leukemia (2012) 2245 – 2253 & 2012 Macmillan Publishers Limited Poor outcome of P2RY8-CRLF2 in childhood ALL C Palmi et al 2247 In addition, 194 SR and 286 IR consecutive patients (non-DS and Ph À ) Protocol stratification enrolled in the AIEOP-BFM ALL2000 study and treated in German Centers Patient risk groups were defined as follows. The HR group included 12 (BFM-G) were analyzed by reverse transcriptase PCR (RT-PCR) for P2RY8- patients with any of the following criteria: t(4;11) or MLL/AF4, prednisone CRLF2 rearrangement, as a validation cohort. poor response (X1000 blasts/ml on day 8 peripheral blood after 7 days of Informed consent to participate in the study was obtained for all prednisone and one dose of intrathecal methotrexate on day 1), inability to patients by parents or legal guardians.
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