Oncotarget

Research Papers:

LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients

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Oncotarget. 2015; 6:1569-1581. https://doi.org/10.18632/oncotarget.2807

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Valeria Cazzaniga _, Cristina Bugarin, Michela Bardini, Marco Giordan, Geertruy te Kronnie, Giuseppe Basso, Andrea Biondi, Grazia Fazio and Giovanni Cazzaniga

Abstract

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

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.



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