Bruton's Tyrosine Kinase (BTK) Inhibitor (Ibrutinib)-Suppressed Migration and Invasion of Prostate Cancer.

INTRODUCTION: Bruton's tyrosine kinase (BTK) inhibitors have long been known in the treatment of B-cell malignancies. Recently, BTK inhibitors have also become promising novel treatment reagents for prostate cancer. The current study was designed to investigate expression of BTK in prostate cancer tissues in comparison with benign hyperplasia and effect of BTK inhibitor on prostate cancer cell proliferation, migration and invasion. METHODS: BTK expression was assessed by immunohistochemistry; migration and invasion prostate cancer cell lines (DU145 and PC3) were assessed by Transwell migration and wound-healing assay; cancer cell proliferation was assessed using MTT assay kit; expression of matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) was assessed by immunoblotting. RESULTS: Strong expression of BTK was detected in the prostate cancer tissues, especially in the tumors from prostate cancer patients with bone metastasis. BTK inhibitor (Ibrutinib) significantly inhibited cell proliferation, migration and invasion of prostate cancer cells as well as protein synthesis of MMP-2 and MMP-9 by the tumor cells. Overexpressing BTK could partially but significantly block the inhibitory effect of Ibrutinib on cell proliferation, migration and invasion, and protein synthesis of MMP-2 and MMP-9 of the cancer cells. CONCLUSION: These findings suggested that BTK could serve as not only a biomarker but also a therapeutic target for the prostate cancer and that Ibrutinib may be applied as a therapeutic drug for the prostate cancer.

Prognosis and outcome of patients with acute myeloid leukemia based on FLT3-ITD mutation with or without additional abnormal cytogenetics.

The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) gene mutation is present in ~20% of patients with de novo acute myeloid leukemia (AML). Patients with an FLT3-ITD mutation have a poor prognosis. However, the prognostic function of FLT3-ITD combined with other cytogenetic abnormalities are not clear. In the present study, a retrospective analysis of 103 newly diagnosed patients with AML was performed. The results revealed that the overall survival (OS) and recurrence-free survival (RFS) times were significantly longer in patients with an FLT3-ITD mutation combined with other favorable risk genes, compared with in those patients with a single FLT3-ITD mutation (P=0.0361 and P=0.0426). Sorafenib combined with chemotherapy significantly improved the overall response rate (ORR) when compared with mono-chemotherapy (P=0.039), but no significant differences were observed in the OS and RFS. In conclusion, favorable-risk cytogenetics may improve the clinical outcomes of patients with FLT3-ITD-mutated AML, but adverse-risk cytogenetics may not further worsen the prognosis. Sorafenib combined with chemotherapy may increase the ORR but would not result in a longer OS and RFS.

[Therapeutic Response and Prognosis of Adult Acute Myeloid Leukemia with Chromosome Karyotype Abnormalities].

OBJECTIVE: To investigate the efficacy and prognosis of acute myeloid leukemia (AML) patients with chromosome karyotype abnormalities. METHODS: The clinical features and treatment responses of 91 patients with AML were collected and analyzed retrospectively. The efficacy and survival rate of the AML patients with normal and abnormal chromosome karyotype were compared. RESULTS: Chromosome translocations and monosomal karyotypes were the main heterogeneity of AML. There was no significant difference in complete remission rate and overall response rate between the normal and abnormal karyotype groups, but the recurrence rate was higher in abnormal karyotype group. There was no significant difference in response of AML patients received the standard "3+7 regimen" and pre-excitation chemotherapy in the treatment of normal and abnormal karyotype groups. The relapse free survival time (RFS) was longer in the normal karyotype group, but there was no significant difference in overall survival time (OS). CONCLUSION: The abnormal karyotype of AML is an independent prognostic factor, monosomal karyotype shows a poor prognosis, and the recurrence rate in AML patients with monosomal karyotype is higher.

Long-term effect of all-trans retinoic acid and arsenic trioxide sequential maintenance in patients with acute promyelocytic leukemia.

The specific prognostic factors and the long-term effects of different treatment options in APL remain unclear. In this retrospective study, 70 APL patients were treated with ATRA + DNR/DA or ATRA + ATO regimens for induction therapy and DA or ATRA + ATO for consolidation and maintenance therapy. The prognostic factors and treatment effects on outcome were analyzed. Results showed that the 5-year OS in low-intermediate risk and high risk groups were 95.63% and 100%, and the 5-year RFS were 95.34% and 100%, respectively, the early mortality rate was 4.28%. No significant difference was found on OS and RFS with different regimens, but side-effects and treatment-related mortality rates were lower in ATRA + ATO group. CD34 expression, FLT3-ITD mutation and PML-RARA isoform had no significance on OS and RFS. In conclusion, cytogenetic and molecular abnormalities had no influence on effect of APL patients; ATRA + ATO sequential maintenance may alleviate complications, treatment-related mortality, and the previously high risk factors.

[Differential Regulation of Bruton's Tyrosine Kinase by the Ubiquitin Pathway].

OBJECTIVE: To investigate the regulation of Bruton's tyrosine kinase (Btk) and to explore its possible mechanism. METHODS: After treatment with the proteasome inhibitors and/or phorbol esters (PMA), the mRNA and protein expression level of Btk was detected by RT-PCR and Western blot, respectively. The ubiquitination level of Btk in B lymphoblastoid A20 cells was estimated after stimulation via the crosslinking of BCR with anti-IgM antibody. The cotransfection of COS-7 cell with Btk, ubiquitin and Cbl was performed, then the ubiquitination level of Btk was measured. The Btk ubiquitination level was detected after ectopic expression of ubiquitin transfected with the wild type or triple mutant of Ub (K29R, K48R, K63R) . Mono-ubiquitination of Btk was detected with antibodies preferentially against monovalent ubiquitin; in addition, the protein expression levels of chloroquine-treated stably transfected cells expressing Btk-GFP were detected by Western blot, and quantified with the strength of GFP fluorescence. RESULTS: In the presence of proteasome-specific inhibitors and/or PMA, steady-state levels of Btk protein were reduced due to decrease of transcription. Posttranslational modification of Btk by ubiquitination was observed, which was related with the level of Btk expression and activation. The E3 ubiquitin ligase Cbl, which binds to Btk, was also found to ubiquitinate this kinase. Altogether, the data of this study strongly suggest that Btk is regulated by poly- and/or mono-ubiquitination events. CONCLUSION: The Btk protein is dictated by its expression level through the ubiquitination pathway.