ABSTRACT
Comprehensive theory explaining the relationship between estrogen (E2) and ezrin in metastasis of thyroid cancer remains non-elicited. In vitro results revealed that E2 could stimulate the expression and phosphorylation of ezrin in a time and dose dependent manner. Our data clearly showed that E2 enhanced the migration and invasion of cells, which was reversed by the transfection of cells with ezrin specific siRNA. Further, we observed that Phosphoinositide 3-kinase (PI3K) ROCK-2 are among the kinases responsible for E2 induced phosphorylation of ezrin. Clinical validation of ezrin/phospho-ezrin revealed that phospho-ezrin was intensely expressed in follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), while it was completely absent in follicular adenoma (FA) lesions in which the differentiation of the follicular neoplasms remains subtle. When histology of different carcinomas is correlated with benign FA with respect to phospho-ezrin, we observed that the marker was highly significant (p = 0.0001). 100% sensitivity, specificity and diagnostic accuracy of the above marker in the histological association of FTC, FVPTC with FA, enables us to suggest phospho-ezrin as a diagnostic marker to differentiate the follicular neoplasms. These data are the first to suggest the dynamic regulation of ezrin phosphorylation during metastasis in FTC.
Subject(s)
Carcinoma/pathology , Cytoskeletal Proteins/physiology , Thyroid Neoplasms/pathology , Adenocarcinoma, Follicular/metabolism , Adenocarcinoma, Follicular/pathology , Cytoskeletal Proteins/metabolism , Estrogens/physiology , Humans , Neoplasm Metastasis , Phosphatidylinositol 3-Kinase/metabolism , Phosphorylation , Thyroid Neoplasms/diagnosisABSTRACT
Identification of BCR-ABL1 fusion gene amplification status is critically important in the effective management of chronic myelogenous leukemia (CML) patients. Earlier reports suggested that overexpression of BCR-ABL1 either through amplification of BCR-ABL1 fusion gene or by the up regulation of BCR-ABL1 transcript level might be an early phenomenon in the establishment of IM resistance and disease evolution in CML. In the current study, we performed dual color dual fusion locus specific BCR/ABL1 FISH analysis along with karyotype analysis using GTG banding (G-banding using trypsin and Giemsa) technique in 489 patients with different clinical stages of CML at diagnosis or during the course of the disease to unravel the spectrum of BCR-ABL1 fusion gene amplification status. Among the study group analyzed, it was found that prevalence of occurrence of BCR-ABL1 fusion gene amplification was significantly higher in advanced stages of disease and in IM resistant CML-CP patients when compared to initial stage of disease, de novo CML-CP. Cytogenetic and metaphase FISH characterization on our study samples revealed that BCR-ABL1 fusion gene amplification was occurred through the formation of extra copies Ph chromosomes and isoderived Ph chromosomes. Current study suggests that unrestrained activity of BCR-ABL1 played a vital role in resistance to targeted therapy and disease evolution in CML. In our study population, patients in progressive stage CML and in IM resistant CP with multiple copies of BCR-ABL1 fusion gene displayed a poor response to targeted treatment with IM. Hence, the early identification of BCR-ABL1 fusion gene amplification using FISH technique will lead to improved interventions and outcome in future CML patients.
Subject(s)
Fusion Proteins, bcr-abl , Gene Amplification , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Philadelphia Chromosome , Adolescent , Adult , Aged , Aged, 80 and over , Chromosome Banding , Female , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Humans , In Situ Hybridization, Fluorescence , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Male , Middle AgedABSTRACT
Elucidation of cryptic BCR/ABL1 gene rearrangement is exceptionally important in the clinical diagnosis and prognosis of chronic myelogenous leukemia (CML). Previous reports indicated an adverse prognostic effect of atypical BCR/ABL1 gene rearrangements with submicroscopic ABL1-BCR deletions on derivative chromosome 9 [der(9)] in CML patients. Dual color dual fusion locus-specific BCR/ABL1 fluorescent in situ hybridization (FISH) analysis together with G-banding using trypsin and Giemsa (GTG banding) was performed in 489 patients at different stages of CML to investigate the spectrum of BCR/ABL1 gene rearrangements. Among the study group analyzed, a significantly higher frequency of BCR/ABL1 gene rearrangements that is consistent with der(9) deletion were observed in the blast crisis (BC) phase at 41.67%, followed by the accelerated phase (AP) at 36.84%, the imatinib mesylate (IM)-resistant chronic phase (CP) at 23.08%, and the lowest incidence was found in de novo CP at 16.61%. 1R1G1F (1 red, 1 green, 1 fusion) with concurrent loss of ABL1-BCR fusion gene on der(9) chromosome was the major signal pattern identified in each group. The results from the current study show that this unusual BCR/ABL1 gene rearrangement is one of the steering forces toward disease progression in CML. Patients in AP/BC of CML with der(9) deletion showed poor response to IM therapy; however, patients with der(9) deletion in the early phases of CML responded well to IM treatment. Therefore, the establishment of an atypical FISH signal pattern in CML is of paramount important because it is associated with adverse clinical prognostic implications in advanced stages of the disease.
