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].
Citazione: | 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]. | |
Tipo: | Articolo in rivista - Articolo scientifico | |
Carattere della pubblicazione: | Scientifica | |
Presenza di un coautore afferente ad Istituzioni straniere: | No | |
Titolo: | LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients | |
Autori: | Cazzaniga, V; Bugarin, C; Bardini, M; Giordan, M; Te Kronnie, G; Basso, G; Biondi, A; Fazio, G; Cazzaniga, G | |
Autori: | CAZZANIGA, VALERIA (Primo) FAZIO, GRAZIA (Penultimo) CAZZANIGA, GIOVANNI (Corresponding) | |
Data di pubblicazione: | 2015 | |
Lingua: | English | |
Rivista: | ONCOTARGET | |
Digital Object Identifier (DOI): | http://dx.doi.org/10.18632/oncotarget.2807 | |
Appare nelle tipologie: | 01 - Articolo su rivista |
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Cazzaniga V_Oncotarget 2015.pdf | N/A | Open Access Visualizza/Apri |