Inverse regulation of bridging integrator 1 and BCR-ABL1 in chronic myeloid leukemia
- 140 Downloads
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.
KeywordsChronic myeloid leukemia BCR-ABL1 Bridging integrator 1 Rab interactor 1 AXL
We are grateful to Prof. Maria Alessandra Santucci and Dr. Enrico Bracco for technical and scientific advice. This paper was supported by Italian Ministry of Health, Current Research Funds for IRCCS, CUP E66J12000230001. DC was funded by grants from the following: AIRC “5 per 1000” and AIL.
Conflicts of interest
- 10.Tanida S, Mizoshita T, Ozeki K, Tsukamoto H, Kamiya T, Kataoka H, et al. Mechanisms of cisplatin-induced apoptosis and of cisplatin sensitivity: potential of BIN1 to act as a potent predictor of cisplatin sensitivity in gastric cancer treatment. Int J Surg Oncol. 2012;2012:862879.PubMedPubMedCentralGoogle Scholar
- 26.Mahadevan D, Theiss N, Morales C, Stejskal AE, Cooke LS, Zhu M, et al. Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST). Oncotarget. 2014.Google Scholar
- 28.Arruga F, Messa F, Pradotto M, Bernardoni R, Bracco E, Carturan S, et al. Disabled gene is involved in CML progression and its expression level at diagnosis can predict major molecular response (MMR) to imatinib therapy. Cancer Res (Annual Meeting of the American Association for Cancer Research Abstract). 2010;70(Suppl 1).Google Scholar
- 29.Cilloni D, Pradotto M, Messa F, Arruga F, Bracco E, Carturan S, et al. Identification of Rab5 as a gene involved in chronic myeloid leukemia (CML) progression. Blood (ASH Annual Meeting Abstracts). 2009;114:3470.Google Scholar
- 35.Lu L, Saunders V, Kok CH, Leclercq T, Hughes TP, White DL. Modeling ponatinib resistance in BCR-ABL1+ cell lines: implications for Ponatinib resistance in TKI-resistant and TKI-naïve patients. Blood (ASH Annual Meeting Abstracts). 2014;124(21).Google Scholar