Gfi-1 is the transcriptional repressor of SOCS1 in acute myeloid leukemia cells

ABSTRACT Silencing of SOCS1, a TSG, has been detected in various malignancies, including AML. However, the underlying mechanism of SOCS1 inactivation remains elusive. In this study, we explored the role of histone methylation in SOCS1 expression in AML cells. By ChIP assay, we demonstrated that G9a and SUV39H1, two enzymes catalyzing H3K9 methylation, were physically associated with the SOCS1 promoter, and treatment with chaetocin, a histone methyltransferase inhibitor, suppressed H3K9 methylation on the SOCS1 promoter and enhanced SOCS1 expression. Furthermore, knockdown of G9a and SUV39H1 by siRNA could also induce SOCS1 expression. On the other hand, SOCS1 knockdown by shRNA eliminated chaetocin-induced cell apoptosis. To investigate further whether any transcription factor was involved in H3K9 methylation-related SOCS1 repression, we scanned the sequences of the SOCS1 gene promoter and found two binding sites for Gfi-1, a transcription repressor. By DNA pull-down and ChIP assays, we showed that Gfi-1 directly bound the SOCS1 promoter, and ectopic Gfi-1 expression suppressed STAT5-induced SOCS1 promoter activation. In contrast, Gfi-1 knockdown by shRNA enhanced SOCS1 expression and inhibited STAT5 expression. Moreover, the knockdown of G9a completely rescued the repressive effect of Gfi-1 on STAT5A-induced SOCS1 promoter activation. Collectively, our study indicates that the expression of Gfi-1 contributes to SOCS1 silencing in AML cells through epigenetic modification, and suppression of histone methyltransferase can provide new insight in AML therapy. J. Leukoc. Biol. 95: 000 -000; 2014

Invasive fungal sinusitis in patients with hematological malignancy: 15 years experience in a single university hospital in Taiwan

<p>Abstract</p> <p>Background</p> <p>Risk factors and outcomes in hematological patients who acquire invasive fungal sinusitis (IFS) are infrequently reported in the modern medical era.</p> <p>Method</p> <p>A retrospective study of hospitalized patients with hematological disease was conducted at National Taiwan University Hospital between January 1995 and December 2009.</p> <p>Results</p> <p>Clinical characteristics and outcomes with their associated radiographic and microbiological findings were analyzed. Forty-six patients with IFS and 64 patients with chronic non-invasive sinusitis were enrolled as comparsion. IFS developed more commonly in patients with acute myeloid leukemia (AML) and with prolonged neutropenia (absolute neutrophil count less than 500/mm³for more than 10 days) (<it>p </it>< 0.001). <it>Aspergillus flavus </it>was the most common pathogen isolated (44%). Serum <it>Aspergillus </it>galactomannan antigen was elevated in seven of eleven patients (64%) with IFS caused by aspergillosis but negative for all three patients with mucormycosis. Bony erosion and extra-sinus infiltration was found in 15 of 46 (33%) patients on imaging. Overall, 19 of 46 patients (41.3%) died within 6 weeks. Patients with disease subtype of AML (p = 0.044; Odds Ratio [OR], 5.84; 95% confidence interval [95% CI], 1.02-30.56) and refractory leukemia status (p = 0.05; OR, 4.27; 95% CI, 1.003-18.15) had worse prognosis. Multivariate analysis identified surgical debridement as an independent good prognostic factor (p = 0.047) in patients with IFS.</p> <p>Conclusions</p> <p>Patients of AML with prolonged neutropenia (> 10 days) had significantly higher risk of IFS. Early introduction of anti-fungal agent and aggressive surgical debridement potentially decrease morbidity and mortality in high risk patients with IFS.</p

Clinical characteristics and outcomes of Mycobacterium tuberculosis disease in adult patients with hematological malignancies

BACKGROUND: Diseases caused by Mycobacterium tuberculosis (TB) among adult patients with hematological malignancies have rarely been investigated. METHODS: Adult patients with hematological malignancies at National Taiwan University Hospital between 1996 and 2009 were retrospectively reviewed. Patients with positive serology for HIV were excluded. TB disease is diagnosed by positive culture(s) in the presence of compatible symptoms and signs. The demographics, laboratory and, microbiological features, were analyzed in the context of clinical outcomes. RESULTS: Fifty-three of 2984 patients (1.78%) were diagnosed with TB disease. The estimated incidence was 120 per 100,000 adult patients with hematological malignancies. Patients with acute myeloid leukemia had a significantly higher incidence of TB disease than other subtypes of hematological malignancies (2.87% vs. 1.21%, p = 0.002, odds ratio, 2.40; 95% confidence interval, 1.39-4.41). Thirty-eight patients (72%) with non-disseminated pulmonary TB disease presented typically with mediastinal lymphadenopathy (53%), pleural effusion (47%) and fibrocalcific lesions (43%) on chest imaging. The 15 (28%) patients with extra-pulmonary disease had lower rates of defervescence within 72 h of empirical antimicrobial therapy (13% vs 45%, p = 0.03) and a higher 30-day in-hospital mortality (20% vs. 0%, p = 0.004) compared to those with disease confined to the lungs. CONCLUSIONS: TB disease is not uncommon among patients with hematological malignancies in Taiwan. Patients who received a diagnosis of extra-pulmonary TB suffered higher mortality than those with pulmonary TB alone. Clinicians should consider TB in the differential diagnoses of prolonged fever in patients with hematological malignancies, particularly in regions of high endemicity