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

C. Palmi, Angela M. Savino, D. Silvestri, Ilaria Bronzini, G. Cario, Maddalena Paganin, Barbara Buldini, M. Galbiati, Martina U. Muckenthaler, C. Bugarin, Pamela Della Mina, Stefan Nagel, Elena Barisone, Fiorina Casale, Franco Locatelli, Luca Lo Nigro, Concetta Micalizzi, R. Parasole, Andrea Pession, M. C. PuttiN. Santoro, Anna Testi, Ottavio Ziino, Andreas E. Kulozik, Martin Zimmermann, M. Schrappe, Antonello Villa, G. Gaipa, Giuseppe Basso, A. Biondi, M. G. Valsecchi, M. Stanulla, V. Conter, G. T. Kronnie, Giovanni Cazzaniga

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)59260-59272
Number of pages13
JournalOncotarget
Volume7
Issue number37
DOIs
Publication statusPublished - 2016

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Pediatrics
Complementary Therapies
Disease-Free Survival
Cytoplasm
Recurrence
Messenger RNA
Survival
Incidence

Keywords

  • CRLF2
  • High risk
  • Pediatric leukemia
  • Prognostic marker
  • T acute lymphoblastic leukemia

ASJC Scopus subject areas

  • Oncology

Cite this

Palmi, C., Savino, A. M., Silvestri, D., Bronzini, I., Cario, G., Paganin, M., ... Cazzaniga, G. (2016). CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia. Oncotarget, 7(37), 59260-59272. https://doi.org/10.18632/oncotarget.10610

CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia. / Palmi, C.; Savino, Angela M.; Silvestri, D.; Bronzini, Ilaria; Cario, G.; Paganin, Maddalena; Buldini, Barbara; Galbiati, M.; Muckenthaler, Martina U.; Bugarin, C.; Mina, Pamela Della; Nagel, Stefan; Barisone, Elena; Casale, Fiorina; Locatelli, Franco; Nigro, Luca Lo; Micalizzi, Concetta; Parasole, R.; Pession, Andrea; Putti, M. C.; Santoro, N.; Testi, Anna; Ziino, Ottavio; Kulozik, Andreas E.; Zimmermann, Martin; Schrappe, M.; Villa, Antonello; Gaipa, G.; Basso, Giuseppe; Biondi, A.; Valsecchi, M. G.; Stanulla, M.; Conter, V.; Kronnie, G. T.; Cazzaniga, Giovanni.

In: Oncotarget, Vol. 7, No. 37, 2016, p. 59260-59272.

Research output: Contribution to journalArticle

Palmi, C, Savino, AM, Silvestri, D, Bronzini, I, Cario, G, Paganin, M, Buldini, B, Galbiati, M, Muckenthaler, MU, Bugarin, C, Mina, PD, Nagel, S, Barisone, E, Casale, F, Locatelli, F, Nigro, LL, Micalizzi, C, Parasole, R, Pession, A, Putti, MC, Santoro, N, Testi, A, Ziino, O, Kulozik, AE, Zimmermann, M, Schrappe, M, Villa, A, Gaipa, G, Basso, G, Biondi, A, Valsecchi, MG, Stanulla, M, Conter, V, Kronnie, GT & Cazzaniga, G 2016, 'CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia', Oncotarget, vol. 7, no. 37, pp. 59260-59272. https://doi.org/10.18632/oncotarget.10610
Palmi, C. ; Savino, Angela M. ; Silvestri, D. ; Bronzini, Ilaria ; Cario, G. ; Paganin, Maddalena ; Buldini, Barbara ; Galbiati, M. ; Muckenthaler, Martina U. ; Bugarin, C. ; Mina, Pamela Della ; Nagel, Stefan ; Barisone, Elena ; Casale, Fiorina ; Locatelli, Franco ; Nigro, Luca Lo ; Micalizzi, Concetta ; Parasole, R. ; Pession, Andrea ; Putti, M. C. ; Santoro, N. ; Testi, Anna ; Ziino, Ottavio ; Kulozik, Andreas E. ; Zimmermann, Martin ; Schrappe, M. ; Villa, Antonello ; Gaipa, G. ; Basso, Giuseppe ; Biondi, A. ; Valsecchi, M. G. ; Stanulla, M. ; Conter, V. ; Kronnie, G. T. ; Cazzaniga, Giovanni. / CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia. In: Oncotarget. 2016 ; Vol. 7, No. 37. pp. 59260-59272.
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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.",
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T1 - CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia

AU - Palmi, C.

AU - Savino, Angela M.

AU - Silvestri, D.

AU - Bronzini, Ilaria

AU - Cario, G.

AU - Paganin, Maddalena

AU - Buldini, Barbara

AU - Galbiati, M.

AU - Muckenthaler, Martina U.

AU - Bugarin, C.

AU - Mina, Pamela Della

AU - Nagel, Stefan

AU - Barisone, Elena

AU - Casale, Fiorina

AU - Locatelli, Franco

AU - Nigro, Luca Lo

AU - Micalizzi, Concetta

AU - Parasole, R.

AU - Pession, Andrea

AU - Putti, M. C.

AU - Santoro, N.

AU - Testi, Anna

AU - Ziino, Ottavio

AU - Kulozik, Andreas E.

AU - Zimmermann, Martin

AU - Schrappe, M.

AU - Villa, Antonello

AU - Gaipa, G.

AU - Basso, Giuseppe

AU - Biondi, A.

AU - Valsecchi, M. G.

AU - Stanulla, M.

AU - Conter, V.

AU - Kronnie, G. T.

AU - Cazzaniga, Giovanni

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

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KW - Pediatric leukemia

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