LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients.
Oncotarget
; 6(3): 1569-81, 2015 Jan 30.
Article
in En
| MEDLINE
| ID: mdl-25595912
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 hyper-activation, and down-regulation of its negative regulator Csk, lead to STAT5 hyper-activation 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
/
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
/
STAT5 Transcription Factor
/
PAX5 Transcription Factor
Type of study:
Prognostic_studies
Limits:
Adolescent
/
Animals
/
Child
/
Child, preschool
/
Female
/
Humans
/
Infant
/
Male
Language:
En
Journal:
Oncotarget
Year:
2015
Document type:
Article
Affiliation country:
Italia