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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.

SUBMITTER: Palmi C

PROVIDER: S-EPMC5312310 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Palmi Chiara C Savino Angela M AM Silvestri Daniela D Bronzini Ilaria I Cario Gunnar G Paganin Maddalena M Buldini Barbara B Galbiati Marta M Muckenthaler Martina U MU Bugarin Cristina C Della Mina Pamela P Nagel Stefan S Barisone Elena E Casale Fiorina F Locatelli Franco F Lo Nigro Luca L Micalizzi Concetta C Parasole Rosanna R Pession Andrea A Putti Maria C MC Santoro Nicola N Testi Anna M AM Ziino Ottavio O Kulozik Andreas E AE Zimmermann Martin M Schrappe Martin M Villa Antonello A Gaipa Giuseppe G Basso Giuseppe G Biondi Andrea A Valsecchi Maria G MG Stanulla Martin M Conter Valentino V Te Kronnie Geertruy G Te Kronnie Geertruy G Cazzaniga Giovanni G

Oncotarget 20160901 37

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); ...[more]

PMID: 27449287

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Project description:It has been reported that overexpression of the CRLF2 gene is associated with poor outcomes in pediatric B cell acute lymphoblastic leukemia (B-ALL), but the incidence rates, clinical characteristics and outcomes of CRLF2 gene overexpression in pediatric T cell ALL (T-ALL) have not been systematically analyzed. In this study, CRLF2 mRNA expression levels and clinical and laboratory parameters in 63 pediatric T-ALL patients were detected at the Children's Hospital of Chongqing Medical University and Children's Hospital of Xianyang between February 2015 and June 2018. The patients were treated according to the modified St. Jude TXV ALL protocol, and early treatment responses (bone marrow smear and MRD level) and prognoses in the enrolled patients were assessed. CRLF2 overexpression was detected in 21/63 (33.33%) patients. Statistical differences were not found for clinical or laboratory parameters (including sex, age, initial WBC count, incidence mediastinal involvement, abnormal karyotype and fusion genes) between patients with high CRLF2 expression and patients with low expression of CRLF2 (P>0.05). One patient died of tumor lysis syndrome and renal failure, and the treatment response was monitored on day 19 (TP1) of remission in 62 patients. One patient quit treatment because of family decisions, and 61 patients underwent treatment response evaluation on day 46 (TP2) of remission. Significant differences were not found between patients with high CRLF2 expression and patients with low CRLF2 expression in terms of the treatment responses at TP1 or TP2 (P>0.05). Following October 2018, 12 patients among the 61 evaluable patients relapsed (relapse rate: 19.67%), 3 patients died from chemotherapy, and the treatment-related mortality (TRM) rate was 4.92%. Secondary tumors occurred in 1 patient. The 3-year prospective EFS rate was 54.1±11.2% and 77.7±6.6% for the 61 evaluable patients and 58 patients without TRM. Patients with low CRLF2 expression had longer EFS durations than patients with high CRLF2 expression (61 evaluable patients: 35.91± 2.38 months vs 23.43± 2.57 months; 58 patients without TRM: 37.86± 2.08 months vs 24.55±2.43 months, P<0.05). CRLF2 expression levels were also monitored in 13 patients at TP1 and TP2, and the MRD level did not vary with the CRLF2 expression level. Our data suggest that clinical features, laboratory findings and treatment responses in the pediatric T-ALL population do not vary based on the overexpression of CRLF2 but that CRLF2 overexpression can contribute to a high risk of relapse in pediatric T-ALL. Thus, CRLF2 expression levels should not be used as biomarkers for monitoring MRD.

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

Publications

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

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