The PAX5 gene is altered in 30% of BCP-ALL patients and PAX5 chromosomal translocations account for 2-3% of cases. Although PAX5 fusion genes significantly affect the transcription of PAX5 target genes, their role in sustaining leukemia cell survival is poorly understood. In an in vitro model of PAX5/ETV6 leukemia, we demonstrated that Lck hyperactivation, and down-regulation of its negative regulator Csk, lead to STAT5 hyperactivation and consequently to the up-regulation of the downstream effectors, cMyc and Ccnd2. More important, cells from PAX5 translocated patients show LCK up-regulation and over-activation, as well as STAT5 hyper-phosphorylation, compared to PAX5 wt and PAX5 deleted cases. As in BCR/ABL1 positive ALL, the hyper-activation of STAT5 pathway can represent a survival signal in PAX5 translocated cells, alternative to the pre-BCR, which is down-regulated. The LCK inhibitor BIBF1120 selectively reverts this phenomenon both in the murine model and in leukemic primary cells. LCK inhibitor could therefore represent a suitable candidate drug to target this subgroup of ALL patients.

Cazzaniga, V., Bugarin, C., Bardini, M., Giordan, M., Te Kronnie, G., Basso, G., et al. (2015). LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients. ONCOTARGET, 6(3), 1569-1581 [10.18632/oncotarget.2807].

LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients

CAZZANIGA, VALERIA
Primo
;
BARDINI, MICHELA;BIONDI, ANDREA;FAZIO, GRAZIA
Penultimo
;
Cazzaniga, G.
2015

Abstract

The PAX5 gene is altered in 30% of BCP-ALL patients and PAX5 chromosomal translocations account for 2-3% of cases. Although PAX5 fusion genes significantly affect the transcription of PAX5 target genes, their role in sustaining leukemia cell survival is poorly understood. In an in vitro model of PAX5/ETV6 leukemia, we demonstrated that Lck hyperactivation, and down-regulation of its negative regulator Csk, lead to STAT5 hyperactivation and consequently to the up-regulation of the downstream effectors, cMyc and Ccnd2. More important, cells from PAX5 translocated patients show LCK up-regulation and over-activation, as well as STAT5 hyper-phosphorylation, compared to PAX5 wt and PAX5 deleted cases. As in BCR/ABL1 positive ALL, the hyper-activation of STAT5 pathway can represent a survival signal in PAX5 translocated cells, alternative to the pre-BCR, which is down-regulated. The LCK inhibitor BIBF1120 selectively reverts this phenomenon both in the murine model and in leukemic primary cells. LCK inhibitor could therefore represent a suitable candidate drug to target this subgroup of ALL patients.
Articolo in rivista - Articolo scientifico
Leucemia lifoblastica acuta, PAX5, STAT5, LCK
English
2015
1569
1581
13
Cazzaniga, V., Bugarin, C., Bardini, M., Giordan, M., Te Kronnie, G., Basso, G., et al. (2015). LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients. ONCOTARGET, 6(3), 1569-1581 [10.18632/oncotarget.2807].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/66148
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