LCKover-expression drives STAT5 oncogenic signaling inPAX5translocated BCP-ALL patients

// Valeria Cazzaniga 1 , Cristina Bugarin 1 , Michela Bardini 1 , Marco Giordan 2 , Geertruy te Kronnie 2 , Giuseppe Basso 2 , Andrea Biondi 1 , Grazia Fazio 1, * , Giovanni Cazzaniga 1, * 1 Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza 20900, Italy 2 Laboratory of Oncohematology, Department of Women’s and Children’s Health, University of Padova, Padova 35128, Italy * These authors contributed equally to this work Correspondence to: Giovanni Cazzaniga, e-mail: gianni.cazzaniga@hsgerardo.org Andrea Biondi, e-mail: abiondi.unimib@gmail.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 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.