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

Chiara Palmi; Angela M. Savino; Daniela Silvestri; Ilaria Bronzini; Gunnar Cario; Maddalena Paganin; Barbara Buldini; Marta Galbiati; Martina U. Muckenthaler; Cristina Bugarin; Pamela Della Mina; Stefan Nagel; Elena Barisone; Fiorina Casale; Franco Locatelli; Luca Lo Nigro; Concetta Micalizzi; Rosanna Parasole; Andrea Pession; Maria C. Putti; Nicola Santoro; Anna M. Testi; Ottavio Ziino; Andreas E. Kulozik; Martin Zimmermann; Martin Schrappe; Antonello Villa; Giuseppe Gaipa; Giuseppe Basso; Andrea Biondi; Maria G. Valsecchi; Martin Stanulla; Valentino Conter; Geertruy te Kronnie; Giovanni Cazzaniga

doi:10.18632/oncotarget.10610

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

Chiara Palmi, Angela M. Savino, Daniela Silvestri, Ilaria Bronzini, Gunnar Cario, Maddalena Paganin, Barbara Buldini, Marta Galbiati, Martina U. Muckenthaler, Cristina Bugarin, Pamela Della Mina, Stefan Nagel, Elena Barisone, Fiorina Casale, Franco Locatelli, Luca Lo Nigro, Concetta Micalizzi, Rosanna Parasole, Andrea Pession, Maria C. PuttiNicola Santoro, Anna M. Testi, Ottavio Ziino, Andreas E. Kulozik, Martin Zimmermann, Martin Schrappe, Antonello Villa, Giuseppe Gaipa, Giuseppe Basso, Andrea Biondi, Maria G. Valsecchi, Martin Stanulla, Valentino Conter, Geertruy te Kronnie, Giovanni Cazzaniga^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	59260-59272
Number of pages	13
Journal	Oncotarget
Volume	7
Issue number	37
DOIs	https://doi.org/10.18632/oncotarget.10610
State	Published - 2016
Externally published	Yes

Keywords

CRLF2
High risk
Pediatric leukemia
Prognostic marker
T acute lymphoblastic leukemia

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Palmi, C., Savino, A. M., Silvestri, D., Bronzini, I., Cario, G., Paganin, M., Buldini, B., Galbiati, M., Muckenthaler, M. U., Bugarin, C., Mina, P. D., Nagel, S., Barisone, E., Casale, F., Locatelli, F., Nigro, L. L., Micalizzi, C., Parasole, R., Pession, A., ... 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

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title = "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.",

keywords = "CRLF2, High risk, Pediatric leukemia, Prognostic marker, T acute lymphoblastic leukemia",

author = "Chiara Palmi and Savino, {Angela M.} and Daniela Silvestri and Ilaria Bronzini and Gunnar Cario and Maddalena Paganin and Barbara Buldini and Marta Galbiati and Muckenthaler, {Martina U.} and Cristina Bugarin and Mina, {Pamela Della} and Stefan Nagel and Elena Barisone and Fiorina Casale and Franco Locatelli and Nigro, {Luca Lo} and Concetta Micalizzi and Rosanna Parasole and Andrea Pession and Putti, {Maria C.} and Nicola Santoro and Testi, {Anna M.} and Ottavio Ziino and Kulozik, {Andreas E.} and Martin Zimmermann and Martin Schrappe and Antonello Villa and Giuseppe Gaipa and Giuseppe Basso and Andrea Biondi and Valsecchi, {Maria G.} and Martin Stanulla and Valentino Conter and Kronnie, {Geertruy te} and Giovanni Cazzaniga",

year = "2016",

doi = "10.18632/oncotarget.10610",

language = "אנגלית",

volume = "7",

pages = "59260--59272",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals LLC",

number = "37",

}

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, AM, 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

TY - JOUR

T1 - CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia

AU - Palmi, Chiara

AU - Savino, Angela M.

AU - Silvestri, Daniela

AU - Bronzini, Ilaria

AU - Cario, Gunnar

AU - Paganin, Maddalena

AU - Buldini, Barbara

AU - Galbiati, Marta

AU - Muckenthaler, Martina U.

AU - Bugarin, Cristina

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, Rosanna

AU - Pession, Andrea

AU - Putti, Maria C.

AU - Santoro, Nicola

AU - Testi, Anna M.

AU - Ziino, Ottavio

AU - Kulozik, Andreas E.

AU - Zimmermann, Martin

AU - Schrappe, Martin

AU - Villa, Antonello

AU - Gaipa, Giuseppe

AU - Basso, Giuseppe

AU - Biondi, Andrea

AU - Valsecchi, Maria G.

AU - Stanulla, Martin

AU - Conter, Valentino

AU - Kronnie, Geertruy te

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.

KW - CRLF2

KW - High risk

KW - Pediatric leukemia

KW - Prognostic marker

KW - T acute lymphoblastic leukemia

UR - http://www.scopus.com/inward/record.url?scp=84991390931&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.10610

DO - 10.18632/oncotarget.10610

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C2 - 27449287

AN - SCOPUS:84991390931

SN - 1949-2553

VL - 7

SP - 59260

EP - 59272

JO - Oncotarget

JF - Oncotarget

IS - 37

ER -

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

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Keywords

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