88 research outputs found
Il contributo degli indicatori di performance all'aziendalizzazione delle produzioni sanitarie
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Galactomannan detection in Geotrichum capitatum invasive infections: report of 2 new cases and review of diagnostic options
No full textWe report 2 cases of Geotrichum capitatum infection in leukemia patients for which Aspergillus galactomannan (GM) assay was positive. The diagnostic options of G. capitatum infections in hematologic patients were reviewed. Although the pathogen was isolated from blood in 77% of cases, diagnostic difficulties remain and GM assay may have a role. (C) 2008 Elsevier Inc. All rights reserved
Chibby 1: A new component of β-catenin-signaling in chronic myeloid leukemia
No full textChibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as β-catenin antagonist. CBY1 is encoded by C22orf2 (22q13.1) Its antagonistic function on β-catenin involves the direct interaction with: the C-terminal activation domain of β-catenin, which hinders β-catenin binding with Tcf/Lef transcription factors hence repressing β-catenin transcriptional activation; 14-3-3 scaffolding proteins (σ or ξ), which drive CBY1 nuclear export into a stable tripartite complex with β-catenin. The relative proximity of C22orf2 gene encoding for CBY1 to the BCR breakpoint on chromosome 22q11, whose translocation and rearrangement with the c-ABL is the causative event of chronic myeloid leukemia (CML), suggested that gene haploinsufficiency may play a role in the disease pathogenesis and progression. We found CBY1 down-modulation associated with the BCR-ABL1, promoted by transcriptional mechanisms (promoter hyper-methylation) and post-transcriptional events, addressing the protein towards proteasome-dependent degradation through SUMOylation. CBY1 reduced expression in clonal progenitors and, more importantly, in leukemic stem cells (LSC), is contingent upon the tyrosine kinase (TK) activity of BCR-ABL1 fusion protein. Accordingly, its induction by Imatinib (IM) and second generation TK inhibitors contributes to β-catenin inactivation through multiple events encompassing the activation of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) and autophagy, eventually leading to apoptotic death. These findings support the advantage of combined regimens including drugs targeting DNA epigenetics and/or proteasome to eradicate the BCR-ABL1+ hematopoiesis
Essential Thrombocythemia: The Dermatologic Point of View
No full textEssential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by an increase in blood platelets and dominated by a predisposition to vascular events. Cutaneous manifestations can complicate its course. itching has been the most common symptom reported; however, the percentage has ranged from 3% to 46%, depending on the survey. Erythromelalgia is found in 6% of cases, and livedo reticularis, minor bleeding, acrocyanosis, and Raynaud's phenomenon are rare manifestations. It is important to recognize and treat these events, because they can affect patients' quality of life and could worsen the prognosis. In addition to skin involvement as a possible sign of ET, the treatment of ET can be associated with cutaneous complications. Hydroxycarbamide, interferon-alfa, and anagrelide can induce different skin lesions. Hydroxycarbamide has been associated with major complications, including painful leg ulcers and actinic keratoses. Minor events include alopecia and hyperpigmentation. Xerosis, pruritus, and photosensitivity are some of the complications reported by patients treated with interferon-alfa. Anagrelide has proved to be associated with fewer dermatologic effects, only detected in single cases. Knowledge of the ET cutaneous manifestations, together with the clinical examination findings, can result in an earlier diagnosis and the start of effective treatment
A calpain-cleaved fragment of β-catenin promotes BCRABL1+ cell survival evoked by autophagy induction in response to imatinib
No full textAutophagy protects chronic myeloid leukemia stem cells from tyrosine kinase inhibitors hence supporting the disease persistence under therapy. However, the signals involved in autophagy regulation relative to BCR-ABL1 are still elusive. The autophagic flux proceeding from the inhibition of BCR-ABL1 tyrosine kinase represents a regulatory mechanism of β-catenin stability through events encompassing the activation of calpain, which targets β-catenin for proteasome-independent degradation. Accordingly, its inactivation may contribute to induce autophagy and autophagy induction may, in turn, promote β-catenin autolysosomal degradation to originate a regulatory loop where β-catenin plays a central role in cell decision between life and death. Here we proved that the cytoplasmic accumulation of β-catenin driven by up-regulation of its antagonist Chibby1 is a component of autophagy induction in response to imatinib in BCR-ABL1+ cells opposing the apoptotic death. It is contingent upon ER stress and elevation of free Ca(2+) cytosolic concentration and results in the calpain cleavage into a 28kDa fragment implicated in β-catenin proteasome-independent degradation. More important for BCR-ABL1+ cell survival and proliferation following IM treatment, might be the calpain-mediated cleavage of β-catenin accumulated within the cytoplasmic compartment into a 75kDa fragment, still owning TCF-dependent transcriptional activity. Such a β-catenin fragment might be crucial for BCR-ABL1+ cell survival following the fusion protein TK inhibition
Chibby drives β catenin cytoplasmic accumulation leading to activation of the unfolded protein response in BCR-ABL1+ cells
No full textAbstractChronic myeloid leukemia (CML) is a myeloproliferative disease caused by the constitutive tyrosine kinase (TK) activity of the BCR-ABL fusion protein. However, the phenotype of leukemic stem cells (LSC) is sustained by β catenin rather than by the BCR-ABL TK. β catenin activity in CML is contingent upon its stabilization proceeding from the BCR-ABL-induced phosphorylation at critical residues for interaction with the Adenomatous polyposis coli (APC)/Axin/glycogen synthase kinase 3 (GSK3) destruction complex or GSK3 inactivating mutations. Here we studied the impact of β catenin antagonist Chibby (CBY) on β catenin signaling in BCR-ABL1+ cells. CBY is a small conserved protein which interacts with β catenin and impairs β catenin-mediated transcriptional activation through two distinct molecular mechanisms: 1) competition with T cell factor (TCF) or lymphoid enhancer factor (LEF) for β catenin binding; and 2) nuclear export of β catenin via interaction with 14-3-3. We found that its enforced expression in K562 cell line promoted β catenin cytoplasmic translocation resulting in inhibition of target gene transcription. Moreover, cytoplasmic accumulation of β catenin activated the endoplasmic reticulum (ER) stress-associated pathway known as unfolded protein response (UPR). CBY-driven cytoplasmic accumulation of β catenin is also a component of BCR-ABL1+ cell response to the TK inhibitor Imatinib (IM). It evoked the UPR activation leading to the induction of BCL2-interacting mediator of cell death (BIM) by UPR sensors. BIM, in turn, contributed to the execution phase of apoptosis in the activation of ER resident caspase 12 and mobilization of Ca2+ stores
DNA methyltransferase 1 drives transcriptional down-modulation of β catenin antagonist Chibby1 associated with the BCR-ABL1 gene of chronic myeloid leukemia.
No full textThe decrease of Chibby1 (CBY1) contributes to β catenin constitutive activation associated with the presence of the BCR-ABL1 fusion gene of chronic myeloid leukemia (CML). This is mediated by transcriptional events and driven by DNA hyper-methylation at promoter-associated CpG islands of the CBY1-encoding gene C22orf2. Moreover, CBY1 transcriptional induction proceeding from promoter de-methylation is a component of BCR-ABL1+ cell response to Imatinib (IM). Our study showed that DNA methyltransferase 1 (DNMT1) has a central role in the hyper-methylation at the C22orf2 promoter. Further investigation in leukemic hematopoietic progenitors from IM-responsive and IM-resistant CML patients at diagnosis failed to demonstrate any correlation between DNMT1-driven hyper-methylation of the C22orf2 promoter and response to IM. Notably, the response to IM was neither predicted by DNMT1-driven hyper-methylation of BCL2-like11 at diagnosis. In conclusion, the hypermethylation of C22orf2 and BCL2-like11 promoters proceeding from DNMT1 is a crucial component of their reduced expression, but it is not directly involved in CML resistance to IM. It might rather contribute to the disease evolution towards a drug-resistant phenotype in more advanced phases or blast crisis
FOXM1 Transcription Factor Is a Component of Beta Catenin Signaling in Hematopoietic Progenitors of Chronic Myeloid Leukemia
No full textPonatinib treatment in chronic myeloid leukemia cell lines targets aurora kinase A/FOXM1 axis
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