期刊
ONCOTARGET
卷 6, 期 3, 页码 1569-1581出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2807
关键词
PAX5; ETV6; LCK; STAT5; BCP-ALL
资金
- Associazione Italiana Ricerca sul Cancro (AIRC)
- Fondazione Cariplo
- Progetto InterBiomed Lombardia
- FIRB-MIUR
- Societa Itailana Ematologia Sperimentale (SIES)
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.
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