LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients
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Valeria Cazzaniga1, Cristina Bugarin1, Michela Bardini1, Marco Giordan2, Geertruy te Kronnie2, Giuseppe Basso2, Andrea Biondi1, Grazia Fazio1,*, Giovanni Cazzaniga1,*
1Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza 20900, Italy
2Laboratory of Oncohematology, Department of Women’s and Children’s Health, University of Padova, Padova 35128, Italy
*These authors contributed equally to this work
Giovanni Cazzaniga, e-mail: firstname.lastname@example.org
Andrea Biondi, e-mail: email@example.com
Keywords: PAX5, ETV6, LCK, STAT5, BCP-ALL
Abbreviations: BCP-ALL, B cell precursors acute lymphoblastic leukemia; wt, wild type; BCR, B cell receptor; IL7, interleukin 7; IL7R, IL7 receptor
Received: August 14, 2014 Accepted: November 25, 2014 Published: January 08, 2015
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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