Inverse regulation of bridging integrator 1 and BCR-ABL1 in chronic myeloid leukemia

Stefania Trino, Luciana de Luca, Vittorio Simeon, Ilaria Laurenzana, Annalisa Morano, Antonella Caivano, Francesco la Rocca, Giuseppe Pietrantuono, Gabriella Bianchino, Vitina Grieco, Elisabetta Signorino, Alberto Fragasso, Maria Teresa Bochicchio, Claudia Venturi, Gianantonio Rosti, Giovanni Martinelli, Luigi Del Vecchio, Daniela Cilloni, Pellegrino Musto

Research output: Contribution to journalArticlepeer-review

Abstract

Endocytosis is the major regulator process of tyrosine kinase receptor (RTK) functional activities. Bridging integrator 1 (BIN1) is a key protein involved in RTK intracellular trafficking. Here, we report, by studying 34 patients with chronic myeloid leukemia (CML) at diagnosis, that BIN1 gene is downregulated in CML as compared to healthy controls, suggesting an altered endocytosis of RTKs. Rab interactor 1 (RIN1), an activator of BIN1, displayed a similar behavior. Treatment of 57 patients by tyrosine kinase inhibitors caused, along with BCR-ABL1 inactivation, an increase of BIN1 and RIN1 expression, potentially restoring endocytosis. There was a significant inverse correlation between BIN1-RIN1 and BCR-ABL1 expression. In vitro experiments on both CML and nontumorigenic cell lines treated with Imatinib confirmed these results. In order to provide another proof in favor of BIN1 and RIN1 endocytosis function in CML, we demonstrated that Imatinib induced, in K562 cell line, BIN1-RIN1 upregulation accompanied by a parallel AXL receptor internalization into cytoplasmic compartment. This study shows a novel deregulated mechanism in CML patients, indicating BIN1 and RIN1 as players in the maintenance of the abnormal RTK signaling in this hematological disease.

Original languageEnglish
JournalTumor Biology
DOIs
Publication statusAccepted/In press - Jul 21 2015

Keywords

  • AXL
  • BCR-ABL1
  • Bridging integrator 1
  • Chronic myeloid leukemia
  • Rab interactor 1

ASJC Scopus subject areas

  • Cancer Research

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