Wilms' tumor gene 1 protein represses the expression of the tumor suppressor interferon regulatory factor 8 in human hematopoietic progenitors and in leukemic cells.

Wilms' tumor gene 1 (WT1) is a transcription factor involved in developmental processes. In adult hematopoiesis, only a small portion of early progenitor cells express WT1, whereas most leukemias show persistently high levels, suggesting an oncogenic role. We have previously characterized oncogenic BCR/ABL1 tyrosine kinase signaling pathways for increased WT1 expression. In this study, we show that overexpression of BCR/ABL1 in CD34+ progenitor cells leads to reduced expression of interferon regulatory factor 8 (IRF8), in addition to increased WT1 expression. Interestingly, IRF8 is known as a tumor suppressor in some leukemias and we investigated whether WT1 might repress IRF8 expression. When analyzed in four leukemia mRNA expression data sets, WT1 and IRF8 were anticorrelated. Upon overexpression in CD34+ progenitors, as well as in U937 cells, WT1 strongly downregulated IRF8 expression. All four major WT1 splice variants induced repression, but not the zinc-finger-deleted WT1 mutant, indicating dependence on DNA binding. A reporter construct with the IRF8 promoter was repressed by WT1, dependent on a putative WT1-response element. Binding of WT1 to the IRF8 promoter was demonstrated by chromatin immunoprecipitation. Our results identify IRF8 as a direct target gene for WT1 and provide a possible mechanism for oncogenic effects of WT1 in leukemia.

Deregulation of the Wilms' tumour gene 1 protein (WT1) by BCR/ABL1 mediates resistance to imatinib in human leukaemia cells.

The Wilms' tumour gene 1 (WT1) protein is highly expressed in most leukaemias. Co-expression of WT1 and the fusion protein AML1-ETO in mice rapidly induces acute myeloid leukaemia (AML). Mechanisms behind expression of WT1, as well as consequences thereof, are still unclear. Here, we report that the fusion protein BCR/ABL1 increases expression of WT1 mRNA and protein via the phosphatidylinositol-3 kinase (PI3K)-Akt pathway. Inhibition of BCR/ABL1 or PI3K activity strongly suppressed transcription from WT1 promoter/enhancer reporters. Forced expression of BCR/ABL1 in normal human progenitor CD34+ cells increased WT1 mRNA and protein, further supporting the notion of BCR/ABL1-driven expression of WT1 in human haematopoietic cells. Forced expression of WT1 in K562 cells provided protection against cytotoxic effects of the ABL1 tyrosine kinase inhibitor imatinib, as judged by effects on viability measured by trypan blue exclusion, metabolic activity, annexin V and DAPI (4', 6-diamidino-2-phenylindole) staining. None of the isoforms provided any detectable protection against apoptosis induced by arsenic trioxide and only very weak protection against etoposide, indicating that WT1 interferes with specific apoptotic signalling pathways. Our data demonstrate that WT1 expression is induced by oncogenic signalling from BCR/ABL1 and that WT1 contributes to resistance against apoptosis induced by imatinib.

[Adenomas of the thyroid gland--criteria for pathohistologic diagnosis]. / Adenomi stitne zlijezde--kriteriji u patohistoloskoj dijagnostici.

Adenomas are the frequent tumors of the thyroid gland, which have different histological types, distinct criteria for pathohistological diagnosis, and distinct criteria for differentiation the follicular adenoma from follicular carcinoma of the thyroid gland. Authors have analyzed 63 patients with follicular adenomas of the thyroid gland which were diagnosed and treated at the Central Institute for Tumors and Allied Diseases in Zagreb in the period from 1986 to 1987, and on which had been done serial cuttings of the tumors for pathohistological diagnosis.

[The importance of clinical and histologic variables in the prognosis of medullary carcinoma of the thyroid gland]. / Znacenje nekih klinickih i histoloskih varijabli za prognozu medularnog karcinoma stitne zlijezde.

Patients with medullary thyroid carcinoma (MTC) have aroused considerable interest ever since Horn (1951), Hazarde et al. (1959) and Williams (1966) described MTC as a separate clinicopathologic entity, because this tumor occurs both in families and in association with neural and endocrine abnormalities. This interest also underlines our clinicohistologic study of 31 patients with a histologically demonstrated MTC. The patients have been analyzed at the Central Institute for Tumors and Allied Diseases in Zagreb from 1969 to 1988. The youngest patient was 17, and the oldest one 85 (average 45 years). None of the patients had thyroid carcinoma in his/her family history, or any association with pheochromocytoma or multiple skin and mucosal neurinoma. The men to women ratio was 1:0.94. The prognostic significance of some clinical and histologic variables in patients affected by medullary thyroid carcinoma have been studied. Treatment involved total thyroidectomy with or without neck dissection. Some of the patients were subsequently irradiated or administered chemotherapeutic agents. The data obtained in the study were statistically processed and the statistical differences between the survival rates of the various patient groups were determined by the logrank-test. Of the studied variables (sex, age, tumor size, cervical metastases, tumor structure, cell type, stroma, calcification, number of mitoses, necrosis, bleeding, amyloid content), the following were found to have a prognostic significance: age, tumor size and regional lymph node metastases.