title: LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients.
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.
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza 20900, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cazzaniga
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza 20900, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bugarin
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza 20900, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Bardini
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Padova 35128, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Giordan
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Padova 35128, Italy.
authors.forename: Geertruy
authors.initials: G
authors.lastname: te Kronnie
authors.affiliation: Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova, Padova 35128, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza 20900, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza 20900, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Fazio
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo/Fondazione MBBM, Monza 20900, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D007223:Infant; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051757:PAX5 Transcription Factor; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D000097764:ETS Translocation Variant 6 Protein; C497281:PAX5 protein, human