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.

Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091. Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment. Importantly, PTEN acts as the main tumor suppressive mediator along the USP7-PTEN axis in a p53 dispensable manner. In conclusion, we propose USP7 as a new druggable target in CLL.

BACKGROUNDThe authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all‐trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor‐risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).METHODSTwenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45–100 μg/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for ≥ 2 months were considered evaluable.RESULTSHematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63–550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone.CONCLUSIONSDifferentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life. Cancer 2005;. © 2005 American Cancer Society.

Thymic carcinoma (primary carcinoma of the thymic epithelium; type C thymoma) is a rare malignancy. It usually presents in middle-aged to elderly patients and can exhibit a wide variety of morphologic appearances. Thymic basaloid carcinoma (thymic BC) is a particularly rare subtype, with less than 20 cases published in the English literature, mostly in the form of individual case reports. In this study, we present the clinicopathologic and immunohistochemical features of 12 new cases of thymic BC. There were 10 (83%) men and 2 (17%) women. Ages at the time of initial diagnosis ranged from 34 to 77 years (mean 55 y). The 2 most common manners of presentation were dyspnea on exertion (3 patients) and as an incidental finding on radiographic imaging (2 patients). Tumors ranged in size from 4.4 to 17 cm (mean 10.1 cm). One of 12 cases (8.3%) was associated with a multilocular thymic cyst. Immunohistochemistry was performed in 8 cases. Pan-cytokeratin was positive in all cases. CD117 (c-kit) was positive in 6 of 8 cases (75%), p63 was positive in 7 of 8 cases (88%), p53 was positive in 7 of 8 cases (88%), ranging from <10% to 90%, CD5 was focally positive in 3 of 8 cases (38%), collagen type IV was positive in 4 of 8 cases (50%), and proliferative index, as estimated by Ki67, ranged from <1% to approximately 15%. In 1 of 2 cases with sarcomatoid differentiation, Ki67 was greater than 80% in the sarcomatoid area. Cases were negative for thyroid transcription factor-1 (0 of 8), S-100 (0 of 7), and synaptophysin (0 of 7). Long-term data was available in 8 patients with an average follow-up of 30 months. Five patients died of their disease at an average of 34 months from the time of diagnosis. Of the remaining 3 patients, 1 had a stable recurrence and died at 4 years from unrelated causes, and 2 were alive without the evidence of disease at 12 and 7 months, respectively. Thymic BC, although previously regarded as a low-grade neoplasm, has shown that it is capable of aggressive behavior and significant mortality. In this paper, we review the pertinent literature and discuss the possible relationship of thymic BC with thymic adenoid cystic carcinoma, as well as BCs and adenoid cystic carcinomas at other sites.

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder with systemic symptoms and poor prognosis and is characterized by an abnormal proliferation of polyclonal plasmablasts in the mantle zone of B-cell follicles. The disease is found primarily in chronic HIV carriers and is usually strictly associated with human herpes virus type 8 (HHV-8) coinfection, which is believed to play a key role in the pathogenesis of MCD. The disease is also diagnosed in HIV-negative patients, who are usually elderly or immunosuppressed; however, in about half of these cases, no evidence of HHV8 infection is found. The anti-CD20 monoclonal antibody rituximab is now the preferred treatment for HIV-positive MCD. However, it is not clear whether rituximab is effective in HIV-negative patients with MCD, particularly in the HHV8-positive subset. We report here the clinical and biologic courses of two HIV-negative, HHV8-positive patients with MCD who were treated with rituximab. In both cases, a significant clinical improvement was observed after the first two infusions, which was shortly followed by a drop in HHV8 viremia to undetectable levels. Both patients underwent complete clinical remission, which persisted without relapse at 30 and 9 months of follow-up, respectively. No reactivation of the Kaposi sarcoma found in a lymph node of one of the patients was observed. Our report, along with additional data present in the literature, suggests that rituximab may be an appropriate and safe first-line therapy for HIV-negative, HHV8-positive MCD.