BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the t(9;22) translocation coding for the chimeric protein p210 BCR-ABL. The tumor suppressor phosphatase and tensin homolog (PTEN) has recently been shown to have a critical role in the pathogenesis of CML. Nuclear localization and proper nuclear-cytoplasmic shuttling are crucial for PTEN's tumor suppressive function. In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity. Importantly, we also find that PTEN delocalization induced by BCR-ABL does not occur in the leukemic stem cell compartment due to high levels of PML, a potent inhibitor of HAUSP activity toward PTEN. We therefore identify a new proto-oncogenic mechanism whereby BCR-ABL antagonizes the nuclear function of the PTEN tumor suppressor, with important therapeutic implications for the eradication of CML minimal residual disease.

Genomic aberrations in normal appearing mucosa fields distal from oral potentially malignant lesions.

OBJECTIVES: Oral fields of visually normal and non-dysplastic mucosa (ODFs) may represent the precursors of oral potentially malignant lesions (OPMLs). Aim of the study was to provide new evidence for the concept of the "field carcinogenesis" model by comparing the ODF and OPML genomic aberration profiles obtained by high resolution DNA flow cytometry (hr DNA-FCM) and array-Comparative Genomic Hybridization (a-CGH). A second aim was to investigate if specific CGH aberrations were associated with DNA aneuploidy. METHODS: Nineteen patients with single OPMLs were recruited for the study. In parallel with obtaining samples of OPML tissue from 11 leukoplakias without dysplasia (nd-OPMLs) and 8 with dysplasia (d-OPMLs), we also obtained samples from distant ODFs. DNA aneuploid nuclei detected by hr DNA-FCM were physically separated, based on DNA content, from the DNA diploid components with a DNA-FCM-Sorter. These relatively pure subpopulations of epithelial nuclei were then submitted to DNA extraction and a-CGH for a genome-wide analysis of DNA copy number aberrations (CNAs). RESULTS: The frequencies of DNA aneuploidy (DI ≠ 1) among ODFs and OPMLs were respectively 5.3% and 32%. The DI aneuploid values of ODFs and nd-OPMLs were all near-diploid (DI ≠ 1 and DI ≤ 1.4), while for d-OPMLs were high-aneuploid (DI > 1.4) in 40% of the cases. CNA averages were 1.9 in ODFs and 6.5 in OPMLs. The gain of the chromosomal region 20q13.33-qter was observed in 37% of both ODFs and corresponding OPMLs. Additional common regions included 7p22.2-pter, 11p15.5-pter and 16p13.3-pter where gains were observed. Furthermore, gains of 20q13.31-q13.33 and of 5p13.33-pter and loss of 9p21.3 were detected at high frequency (respectively, at 62.5%, 50% and 50%) only in d-OPMLs. In particular, loss at 9p21.3, gain at 5p13.33-pter and gain of 20q13.31-q13.33 were associated with DNA aneuploidy (p = 0.00004; p = 0.0005; p = 0.01). CONCLUSIONS: ODFs and OPMLs showed common CNAs in specific chromosomal regions suggesting that they may represent early events of the natural history of oral carcinogenesis according to the field effect cancerization and may contribute to the ODF-OPML transition. In addition, loss at 9p21.3 and gains at 5p13.33-pter and 20q13.31-q13.33 may contribute to DNA aneuploidization.

Solitary fibrous tumor of the lung: three rare cases of intraparenchymal nodules.

Solitary fibrous tumor (SFT) of the pleura usually presents as a peripheral mass, in contact with the surface of the pleura. However, on occasion, it can occur separately from the pleura, in the lung parenchyma. We describe the radiological and imaging features of three SFTs of the lung, diagnosed in our department, with relevant clinical data. The diagnosis of SFT of the lung, although rare, should be considered in a slow-growing solitary lung parenchymal nodule.

Fibrous tumour of the pleura (SFTP): a proteiform disease. Clinical, histological and atypical radiological patterns selected among our cases.

First described by Klemperer and Rabin in 1931, solitary fibrous tumour of the pleura (SFTP) is a mesenchymal tumour that tends to involve the pleura, although it has also been described in other thoracic areas (mediastinum, pericardium and pulmonary parenchyma) and in extrathoracic sites (meninges, epiglottis, salivary glands, thyroid, kidneys and breast). SFTP usually presents as a peripheral mass abutting the pleural surface, to which it is attached by a broad base or, more frequently, by a pedicle that allows it to be mobile within the pleural cavity. A precise preoperative diagnosis can be arrived at with a cutting-needle biopsy, although most cases are diagnosed with postoperative histology and immunohistochemical analysis of the dissected sample. SFTP, owing to its large size or unusual locations (paraspinal, para-mediastinal, intra-fissural and intraparenchymal), can pose interpretation problems or, indeed, point towards a diagnosis of diseases of a totally different nature. We present some unusual radiographic and computed tomography (CT) images of large SFTP or SFTP located in atypical thoracic locations in patients who underwent surgical resection.

CT features of solitary fibrous tumour of the pleura: experience in 26 patients.

PURPOSE: The purpose of this study was to identify the typical computed tomography (CT) features of solitary fibrous tumours of the pleura (SFTP) and determine which findings would allow confirmation of the pleural origin or benign behaviour of the tumour. MATERIALS AND METHODS: Twenty-six preoperative CT studies of the chest (23 enhanced and 14 unenhanced) were retrospectively reviewed. RESULTS: Up to 50% of SFTP were larger than 10 cm. At unenhanced CT, they showed homogeneous attenuation in 5 cases (35.7%) and inhomogeneous attenuation in 9 (64.3%). At contrast-enhanced CT, they were inhomogeneous in 21 cases (91.3%), with geographic pattern (61.9% of cases), serpiginous linear areas of enhancement (intralesional vessels) (23.8%), rounded (52.4%) or linear (33.3%) areas of low attenuation (necrosis). CONCLUSIONS: Depending on location, size and histological features, SFTP may produce a large spectrum of findings. Typical CT features of small SFTP were well-defined margins and smooth contours, homogeneous attenuation and right or obtuse angles with the pleura. Larger lesions were characterised by well-defined margins and lobulated contours, geographic pattern in enhanced CT scans, acute angles or smooth tapering margins with the pleura.

[AIDS and the central nervous system: correlations between clinical, radiological and anatomo-pathological aspects. A critical review of 40 personal cases]. / AIDS e sistema nervoso centrale: correlazioni tra aspetti clinici, radiologici ed anatomo-patologici. Resvisione critica di 40 casi di osservazione personale.

The authors review the cases of 40 patients with AIDS who died in 1989, in order to establish the relationships between clinical picture, neuroradiological features and neuropathological findings. Neurological involvement was present in over 75% of the patients, with HIV-related encephalopathy and toxoplasmosis as the most frequent diseases (52.5% and 20.0%). With regard to the cases of AIDS dementia complex (ADC) the authors observed a good correlation between the severity of the clinical manifestations, central nervous system atrophy as observed on computed tomography scan and pathological findings. The survival of AIDS patients with ADC was higher when compared to patients without ADC, suggesting the time-relationship of ADC. AS in the case of toxoplasma encephalitis, a strong relationship between radiological and pathological findings was observed. The presence of toxoplasma encephalitis in patients with radiologic features of healed lesions confirms the need for life-long prophylaxis.

[Visceral leishmaniasis in patients with AIDS. Description of 2 cases]. / Leishmaniosi viscerale in pazienti con AIDS. Descrizione di 2 casi.

Cell-mediated immunity plays a pivotal role in the pathogenesis and in the recovery mechanisms of visceral leishmaniasis (V.L.). This disease, observed in two patients with AIDS, has peculiar anatomical and clinical characteristics and it is usually characterized by a severe clinical course. In addition, V.L. has been proposed to be included among the relevant infections for the case definition of AIDS. We describe two cases of V.L. occurred in association with AIDS. The most relevant characteristics of our cases are the followings: Diagnosis has been achieved by the identification of Leishmania donovani in the macrophages of the bone marrow in both the patients, and of the lymph node in one patient. The detection of anti-Leishmania antibodies was positive in one patients only. A significant defect of CD4+ cells was documented in both the patients. V.L. was associated in one patient with esophageal candidiasis, disseminated tuberculosis, P. carinii pneumonia; and in the other one with cerebral toxoplasmosis, pulmonary tuberculosis, esophageal candidiasis, Kaposi's sarcoma, CMV hepatitis. Specific chemotherapy has been partially or totally ineffective in both the patients. In fact, chemotherapy led to an apparent transient recovery in one patient, followed by a symptom-free period of more than one year. We think that V.L. has been the first infection occurred in this patients, beside of HIV infection. At the time of the first observation, the clinical conditions of this patient were satisfactory and there was only a slight alteration in cellular immunity. The detection of leishmania in bone marrow was coincident with the onset of fever, the development of a wasting syndrome and a dramatic decrease in cell-mediated immunity. A second cycle of specific treatment has been ineffective and the patient died. On the contrary, the second patient did not respond to the specific treatment and died. Two important anatomo-pathological characteristics were present in our cases: a) the presence of the parasite in several organs, namely bone marrow, spleen, liver. b) the absence of granulomatous lesions which indirectly indicates the defect in cell mediated immunity.