Induction of Transcriptional Inhibitor HES1 and the Related Repression of Tumor-Suppressor TXNIP Are Important Components of Cell-Transformation Program Imposed by Oncogenic Kinase NPM-ALK.

This study reports that hairy and enhancer of split homolog-1 (HES1), known to repress gene transcription in progenitor cells of several cell lineages, was strongly expressed in cells and tissues of T-cell lymphoma expressing the oncogenic chimeric tyrosine kinase nucleophosmin (NPM)-anaplastic lymphoma kinase [ALK; ALK+ T-cell lymphoma (TCL)]. The structural analysis of the Orange domain of HES1 indicated that HES1 formed a highly stable homodimer. Of note, repression of HES1 expression led to inhibition of ALK+ TCL cell growth in vivo. The expression of the HES1 gene was induced by NPM-ALK through activation of STAT3, which bound to the gene's promoter and induced the gene's transcription. NPM-ALK also directly phosphorylated HES1 protein. In turn, HES1 up-regulated and down-regulated in ALK+ TCL cells, the expression of numerous genes, protein products of which are involved in key cell functions, such as cell proliferation and viability. Among the genes inhibited by HES1 was thioredoxin-interacting protein (TXNIP), encoding a protein implicated in promotion of cell death in various types of cells. Accordingly, ALK+ TCL cells and tissues lacked expression of TXNIP, and its transcription was co-inhibited by HES1 and STAT3 in an NPM-ALK-dependent manner. Finally, the induced expression of TXNIP induced massive apoptotic cell death of ALK+ TCL cells. The results reveal a novel NPM-ALK-controlled pro-oncogenic regulatory network and document an important role of HES and TXNIP in the NPM-ALK-driven oncogenesis, with the former protein displaying oncogenic and the latter tumor suppressor properties.

Cutting Edge: ROR1/CD19 Receptor Complex Promotes Growth of Mantle Cell Lymphoma Cells Independently of the B Cell Receptor-BTK Signaling Pathway.

Inhibitors of Bruton tyrosine kinase (BTK), a kinase downstream of BCR, display remarkable activity in a subset of mantle cell lymphoma (MCL) patients, but the drug resistance remains a considerable challenge. In this study, we demonstrate that aberrant expression of ROR1 (receptor tyrosine kinase-like orphan receptor 1), seen in a large subset of MCL, results in BCR/BTK-independent signaling and growth of MCL cells. ROR1 forms a functional complex with CD19 to persistently activate the key cell signaling pathways PI3K-AKT and MEK-ERK in the BCR/BTK-independent manner. This study demonstrates that ROR1/CD19 complex effectively substitutes for BCR-BTK signaling to promote activation and growth of MCL cells. Therefore, ROR1 expression and activation may represent a novel mechanism of resistance to inhibition of BCR/BTK signaling in MCL. Our results provide a rationale to screen MCL patients for ROR1 expression and to consider new therapies targeting ROR1 and/or CD19 or their downstream signaling pathways for MCL-expressing ROR1.

Elevated Adenosine Dehydrogenase (ADH) and Positive Tuberculin Test Firstly Misdiagnosed as Tuberculous Pleural Effusion Finally Proved as Pleural Mesothelial Sarcoma by Thoracoscopic Biopsy Pathology: a Case Report and Literature Review.

BACKGROUND: In China, tuberculous pleural effusion is the most common cause for pleural effusion. Elevated ADH and positive tuberculin test usually are characteristic of tuberculous pleural effusion. We reported a 71-year-old male patient with elevated ADH and positive tuberculin test firstly misdiagnosed as tuberculous pleural effusion finally proven as pleural mesothelial sarcoma by thoracoscopic pathology. METHODS: Appropriate laboratory tests and thoracentesis were carried out. Thoracoscopy and pathological biopsy were performed to differentiate tuberculous pleural effusion. RESULTS: Chest CT showed right pleural effusion. ADH in pleural effusion was over 45 U/L and PPD test was positive. No abnormal cells were found in pleural effusion pathology. Pathology of thoracoscopic biopsy proved pleural mesothelioma. CONCLUSIONS: Elevated ADH and positive tuberculin test are not a specific index for tuberculosis and thoracoscopic biopsy pathology is crucial for differential diagnosis.

Right Lung Consolidation Combined Elevated Serum Neuron Specific Enolase Misdiagnosed as Lung Carcinoma Ultimately Confirmed Pulmonary Cryptococcosis by CT-guided Percutaneous Lung Biopsy: a Case Report and Literature Review.

BACKGROUND: Detection of serum neuron specific enolase (NSE) has high sensitivity and specificity in the diagnosis of lung carcinoma, especially in small cell lung carcinoma, but sometimes serum NSE provided limited help. We report a case of a patient with right lung consolidation combined with elevated serum neuron specific enolase which mimicked lung carcinoma and was ultimately confirmed as pulmonary cryptococcosis by CT-guided percutaneous lung biopsy. METHODS: Chest computed tomography (CT) scan and CT-guided percutaneous lung biopsy were performed for diagnosis and blood tests explored the latent etiology. RESULTS: The chest CT scan showed right lung consolidation and a pulmonary nodule in lingual segment of upper lobe of left (Figure1A - F). Serum cryptococcal antigen was positive. Pathology of CT-guided percutaneous lung biopsy confirmed pulmonary cryptococcosis (Figure 1G - I). CONCLUSIONS: Elevated NSE is not a specific index of lung cancer. Serum cryptococcal antigen and CT-guided percutaneous lung biopsy has high specificity in cryptococcal pneumonia.

Hemoptysis and High-Density Shadow of Both Lungs Combined with Elevated Serum G-Lipopolysaccharide Misdiagnosed as Bronchiectasis with Gram-Negative Bacterium Infection Ultimately Confirmed as Mycobacterium Iranicum Infection by CT-guided Percutaneous Lung Biopsy and Next Generation Sequencing (NGS): a Case Report and Literature Review.

BACKGROUND: G-lipopolysaccharide, a component of the cell wall of Gram-negative bacteria, is called lipopolysaccharide. The detection of G-lipopolysaccharide can be used for the early diagnosis of infectious diseases, but some-times G-lipopolysaccharide provides limited help. We report a case of a patient with hemoptysis and high-density shadow of both lungs combined with elevated serum G-lipopolysaccharide which mimicked bronchiectasis with Gram-negative bacterium infection. It was ultimately confirmed as Mycobacterium iranicum infection by CT-guided percutaneous lung biopsy and next generation sequencing. METHODS: The chest computed tomography (CT) scan, CT-guided percutaneous lung biopsy, and NGS were performed for diagnosis and blood tests explored for the latent etiology. RESULTS: The chest CT scan showed a high-density shadow of both lungs, atelectasis of right middle lobe, multiple enlarged lymph nodes in mediastinum and right hilum. Pathology of CT-guided percutaneous lung biopsy indicated fibrous tissue proliferation and granulation tissue formation and some alveolar epithelial cells slightly proliferated with focal carbon powder deposition in alveolar sacs and spaces. The lung tissue NGS confirmed Mycobacterium iranicum infection. CONCLUSIONS: Elevated serum G-lipopolysaccharide is not a specific index for infectious diseases. CT-guided percutaneous lung biopsy and lung tissue NGS has high specificity in pathogen detection of infectious diseases.

Left Lung Neoplasms and Bilateral Pleural Effusion Combined Elevated Carcinoembryonic Antigen in Pleural Effusion with Negative Result of Thoracoscopy Pleural Biopsy Misdiagnosed as Lung Carcinoma Ultimately Confirmed Pulmonary Sarcomatoid Carcinoma by CT-guided Percutaneous Lung Biopsy: a Case Report and Literature Review.

BACKGROUND: Detection of carcinoembryonic Antigen (CEA) in pleural effusion has good clinical application value in differentiating benign and malignant pleural effusion, but sometimes CEA provides limited help. We report a case of a patient with left lung neoplasms combined with bilateral pleural effusion with increased CEA in the pleural effusion whose thoracoscopy pleural biopsy pathology was negative, mimicking lung carcinoma and ultimately confirmed as pulmonary sarcomatoid carcinoma by CT-guided percutaneous lung biopsy. METHODS: The chest computed tomography (CT) scan, thoracoscopy pleural biopsy, and CT-guided percutaneous lung biopsy were arranged to explore the etiology of pleural effusion. RESULTS: The chest CT scan showed bilateral pleural effusion with left lung neoplasms, pulmonary atelectasis, and left hilar enlargement. Pathology of thoracoscopy biopsy showed pleural inflammation with infiltration of inflammatory cells. Pathology of CT-guided percutaneous lung biopsy confirmed pulmonary sarcomatoid carcinoma. CONCLUSIONS: Elevated pleural effusion CEA is not a specific index of lung cancer. CT-guided percutaneous lung biopsy is appropriate for patients presenting with pleural diseases with lung neoplasms, especially when thoracoscopy pleural biopsy result was negative.

Neutrophil-to-Lymphocyte Ratio in Adult Community-Acquired Pneumonia Patients Correlates with Unfavorable Clinical Outcomes.

BACKGROUND: Despite the extensive improvement in antibiotic treatment and medical care, severe adult community-acquired pneumonia (CAP) remains as the significant cause of death worldwide. Earlier prognosis assessment and timely treatment in adult CAP patients are useful for prognosis. The neutrophil-to-lymphocyte ratio (NLR) in blood routine has a broad application possibility in assessing inflammatory reaction and prognosis. The aim of this study was to examine the relationship between NLR and inflammatory reaction and to unravel the usefulness of NLR in the assessment of clinical outcomes in adult CAP patients. METHODS: This retrospective study was conducted based on adult patients with a primary diagnosis of CAP. All patients included received a routine blood test and calculated NLR. All of the measurement data were analyzed with paired t-test and the enumeration data were analyzed with χ2 test. Multivariate analysis was performed to investigate the association between predictors (age, male, CURB-65 scores, comorbidity, NLR, and other inflammatory cells in blood routine) and unfavorable outcomes of CAP (ICU admission and 30-day mortality). Receiver operating characteristic curves (ROC) were used to evaluate the sensitivity and specificity of NLR in predicting unfavorable outcomes of CAP. RESULTS: One hundred fifty patients were included. Compared with favorable outcomes group, age, CURB-65 scores, WBC, neutrophil and lymphocyte counts, and NLR were elevated in unfavorable outcomes group (p < 0.05), gender and coexisting illness did not differ obviously. Multivariate logistic regression model analysis showed CURB-65 scores and NLR were independent predictors correlated with unfavorable outcomes (p < 0.05). The area under the ROC curve (AUC) of NLR was 0.81 (95% CI 0.73 to 0.89), the sensitivity was 81.00% and specificity was 72.8%. NLR is superior to CURB-65 in predicting unfavorable outcomes. NLR combined CURB-65 has better sensitivity and specificity (89.40% versus 91.30%). CONCLUSIONS: NLR is a simple, cheap, and rapidly available measurement in blood routine and is associated with unfavorable clinical outcomes in adult CAP patients.

High Serum Neuron-Specific Enolase (NSE) Level Firstly Ignored as Normal Reaction in a Small Cell Lung Cancer Patient: a Case Report and Literature Review.

BACKGROUND: High serum neuron-specific enolase (NSE) level has been in use as a tumor marker; however, some physicians may ignore NSE levels in serum, especially when the patients are asymptomatic. Here we report a case that a 51 year old female patient with no respiratory symptoms who had a NSE level which increased extremely over three months and was eventually diagnosed small cell lung cancer (SCLC). METHODS: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in right pulmonary hilar enlarged lymph node was performed for diagnosis. RESULTS: EBUS showed right pulmonary hilar lymph node enlargement. A TBNA biopsy histopathology diagnosed SCLC. CONCLUSIONS: We should pay attention to high serum NSE levels, especially when the index increased extremely over a short time.

Anemia Combined Significantly Increased High-Sensitivity C Reactive Protein and Lung Lesions Lead to the Diagnosis of Granulomatosis with Polyangiitis Proven by Lung Biopsy and Anti-neutrophil Cytoplasmic Antibody Test.

Background: To report an atypical case misdiagnosed as lung abscess over the past 2 months, but persistent anemia combined with significantly increased hs-CRP and lung lesions indicated systemic lesion, which led to the diagnosis of granulomatosis with polyangiitis proven by lung biopsy and anti-neutrophil cytoplasmic antibody test (ANCA).

Methods: The complete blood count, hs-CRP, and anti-neutrophil cytoplasmic antibody (ANCA) test were performed. The pathology consultation for the lung biopsy was arranged.

Results: Hemoglobin was 8.5 g/L, hs-CRP was > 200 mg/L, c-ANCA directed against anti-proteinase 3 (PR3) was positive, pathology consultation reported granulomatous inflammation.

 

 

 

 

Conclusions: When patients have multiple organ dysfunction combined with anemia and significantly increased hs-CRP, physicians should pay attention to systemic vasculitis.

Tuberculosis Antibody and Tuberculin Positive Tests Initially Misdiagnosed as Active Tuberculosis in a Broncholithiasis Patient with Recurrent Hemoptysis and Fever Proven by Lung Lobectomy.

BACKGROUND: To report a case of broncholithiasis with recurrent hemoptysis and fever initially misdiagnosed as active tuberculosis. METHODS: The chest contrast-enhanced CT scan, electronic bronchoscope, and ultrathin bronchoscope were performed leading to the diagnosis of broncholithiasis, open lung lobectomy was done after thoracic surgery consultation. RESULTS: The chest contrast-enhanced CT scan showed a high-density intratracheal shadow and calcified lymph nodes. Ultrathin bronchoscopy manifested calcified lesions located at the distal portion of the right lower lobe bronchus. Histopathology of lobectomy showed lithiasis in the right lower lobe tracheobronchial tree. CONCLUSIONS: We should pay attention to calcified intratracheal lesions and make differential diagnosis with tuberculosis, especially when accompanied with calcified lymph nodes and fever.

Elevated Plasma D-Dimer in Adult Community-Acquired Pneumonia Patients is Associated with an Increased Inflammatory Reaction and Lower Survival.

BACKGROUND: Community-acquired pneumonia (CAP) is a common infectious disease. Inflammatory reaction and prognosis assessment in adult CAP patients are useful for CAP site of care decisions. Most CAP patients were diagnosed in an out-patient or emergency department, so a simple, cheap and rapidly available measurement to assess inflammatory reaction and prognosis has the prospect of broad application. The aim of this study was to investigate the usefulness of plasma D-Dimer in assessment of inflammatory reaction and prognosis in adult CAP patients. METHODS: A retrospective study was conducted. All adult patients with a primary diagnosis of CAP were included and were evaluated by peripheral plasma D-Dimer test. All of the measurement data were analyzed with paired t-test and the enumeration data were analyzed with χ2 test. Correlative factor analysis was performed between D-Dimer levels and serum inflammatory markers (WBC, hs-CRP, PCT) and prognostic indexes (ICU admission and 30-day mortality). Receiver operating characteristic curves (ROC) were used to evaluate the sensitivity and specificity of D-Dimer in predicting ICU admission and/or 30-day mortality. RESULTS: One hundred fifty patients were included. Compared with non-D-Dimer elevated group, serum inflammatory markers (WBC, hs-CRP, PCT) and prognostic indexes (ICU admission and 30-day mortality) were elevated in the D-Dimer elevated group (p < 0.05). D-Dimer had positive correlation with serum inflammatory markers (WBC, hs-CRP, PCT), the rates of ICU admission and 30-day mortality, and scores of CURB-65. The AUC of ROC curve of D-Dimer was 0.880 (95% CI 0.823 to 0.936), the sensitivity was 80.4% and specificity was 79.8%, D-Dimer levels are superior to hs-CRP and PCT in predicting 30-day mortality and/or ICU admission according to AUCs of the ROC curves. CONCLUSIONS: Elevated plasma D-Dimer in adult CAP patients is associated with an increased inflammatory reaction and ICU admission and 30-day mortality. It can be a simple, cheap, and rapidly available measurement to assess inflammatory reaction and prognosis in adult CAP patients.

Neutrophil-to-Lymphocyte Ratio Improves the Accuracy and Sensitivity of Pneumonia Severity Index in Predicting 30-Day Mortality of CAP Patients.

BACKGROUND: The pneumonia severity index (PSI) scoring system is one of the tools used to evaluate and predict the prognosis of patients with community-acquired pneumonia (CAP). Although PSI has been widely used in clinical studies of pneumonia, it is still rare to combine it with blood indexes to predict the prognosis of pneumonia. Neutrophil-to-lymphocyte ratio (NLR) is a promising candidate predictor of mortality in CAP patients. The aim of this study was to investigate the efficacy of pneumonia severity index combined with NLR in predicting 30-day mortality in CAP patients. METHODS: We conducted a retrospective study. We analyzed data on 400 non-immune individuals over the age of 18 in this study. All patients received blood routine measurement and PSI score calculation after admission. The primary outcome measures were mortality and survival in CAP patients. The sensitivity and specificity of PSI score, NLR, and the combination of PSI score and NLR in predicting 30-day mortality were assessed using the subject operating characteristic curve (ROC). RESULTS: Data from 400 patients were analyzed, in which the 30-day mortality was 10.5% (42/400). The AUC of NLR and PSI in predicting 30-day mortality of CAP patients were 0.81 (95% CI 0.73 - 0.89) and 0.94 (95% CI 0.90 - 0.98), respectively, with statistically significant differences (p = 0.00). The sensitivity and specificity of NLR were 0.80 and 0.7, respectively. The sensitivity and specificity of PSI were 0.78 and 0.94, respectively. The combined AUC of the two indicators for predicting death in CAP patients was 0.95 (95% CI 0.92 - 0.99), and the sensitivity and specificity were 0.85 and 0.94, respectively. CONCLUSIONS: Neutrophil-to-lymphocyte ratio improves the accuracy and sensitivity of the pneumonia severity index in predicting 30-day mortality of CAP patients.

Elevated Red Blood Cell Distribution Width Combined White Blood Cell in Peripheral Blood Routine Have a Better Sensitivity than CURB-65 Scores in Predicting ICU Admission and Mortality in Adult Community-Acquired Pneumonia Patients.

Background: Scoring systems including CURB-65 and Pneumonia Severity Index (PSI) and novel or traditional biomarkers including procalcitonin (PCT) and c-reactive protein (CRP) are very significant for understanding the severity and prognosis in community-acquired pneumonia (CAP) patients, while prognostic items are useful for CAP prognostication and point-of-care decisions. The aim of this study was to investigate the usefulness of peripheral blood routine items in predicting ICU admission and 30-day mortality in CAP patients.

Methods: A retrospective study was conducted. All adult patients with a primary diagnosis of CAP were included and peripheral blood routine tests were evaluated. Univariate analysis and multivariate logistic regression analysis were used to explore association of risk factors with 30-day mortality among CAP patients. Receiver operating characteristic curves (ROC) were used to evaluate the sensitivity and specificity of peripheral blood routine items and compared with CURB-65 scores in predicting ICU admission and/or 30-day mortality.

Results: One hundred fifty patients were included and compared with non-ICU admission patients. There was a statistically significant difference in age, co-existing illness, RDW, WBC, and CURB-65 scores ranking in ICU admission patients (p < 0.05). In multivariate logistic regression analysis, we found RDW, WBC, and CURB-65 ≥ 3 scores increased the risk of 30-day mortality by 4.01, 1.65, and 3.43 times, respectively. The area under the curve (AUC) of ROC curves of RDW combined with WBC and CURB-65 was 0.786 (95% CI 0.701 to 0.876) and 0.836 (95% CI 0.764 to 0.908), respectively and the sensitivity was 84.0% and 60.0%, respectively, and the specificity 66.7% and 93.7%, respectively.

Conclusions: Elevated RDW and WBC increased mortality in adult CAP patients, RDW combined with WBC had a better sensitivity than CURB-65 scores in predicting ICU admission and/or mortality in CAP patients.

Does Adenovirus and Coxsackie B Virus Infection Play a Role in Tracheobronchopathia Osteochondroplastica (TO).

Background: Tracheobronchopathia osteochondroplastica (TO) is a rare benign disease. We report a case of TO. Methods: Chest CT scan and bronchoscope with biopsy was performed for diagnosis and blood tests explored for the latent etiology. Results: Chest CT scan and bronchoscopic images showed multiple nodular protrusions in the trachea and main bronchi. Histopathology demonstrated sub-mucosal ossification and inflammatory cell infiltration. Laboratory inspection showed adenovirus and coxsackie B virus IgM antibodies were positive. Conclusions: The patient recently had a virus infection and inflammation was observed in histopathology, which indicated adenovirus and coxsackie B virus may play a role in the occurrence or exacerbation of TO.

Serum High-Sensitivity C Reactive Protein Improves Sensitivity of CURB-65 in Predicting ICU Admission and Mortality in Community-Acquired Pneumonia Patients.

BACKGROUND: The CURB-65 scoring system is a simple tool in assessment and prognosis prediction for communityacquired pneumonia (CAP) patients. However, the variations in performance of CURB-65 in young and elderly patients, underestimation or overestimation of the severity, and mortality have often been reported. The aim of this study was to investigate the usefulness of serum high-sensitivity C reactive protein (hs-CRP) combined with CURB-65 in predicting ICU admission and 30-day mortality in CAP patients. METHODS: We conducted a retrospective study. All patients over 18 years of age with a primary diagnosis of CAP were included, all of them received serum hs-CRP test and CURB-65 scaring evaluation. The main outcome measures were ICU admission and 30-day mortality. Receiver operating characteristic curves (ROC) were used to evaluate the sensitivity and specificity of the CURB-65 model and hs-CRP combined CURB-65 augmented model in predicting the main outcomes. RESULTS: Data from 150 patients was analyzed, in which the rate for patients requiring ICU admission was 30.67%, and the ultimate mortality rate was 24%. The areas of ROC curves (AUC) of CURB-65 was 0.859 (95% CI 0.705 to 1.000), hs-CRP combined CURB-65 augmented model was 0.864 (95% CI 0.692 to 1.000), ROC curve analyses showed the augmented model had higher sensitivity than the CURB-65 model in predicting main outcomes (p = 0.001). CONCLUSIONS: Measurement of serum hs-CRP in addition to the CURB-65 model improved the clinical usefulness in predicting ICU admission and mortality in CAP patients.

Serum Cryptococcal Antigen Confirmed Pulmonary Cryptococcosis in an Immune-competent Adult Firstly Misdiagnosed of Tuberculosis from a Lung Biopsy: a Case Report and Literature Review.

Background: Cryptococcal pneumonia is an uncommon lesion in immune-competent adults. Histological evidence of Cryptococcus neoformans is a gold criterion for diagnosis. Here we report a case firstly misdiagnosed as tuberculosis from a lung biopsy. Methods: Chest computed tomography (CT) scan and CT-guided puncture were performed for diagnosis and blood tests explored for the latent etiology. Results: Chest CT scan images showed multiple nodules in the left peripheral lower lobe. Histopathology demonstrated multiple granulomatous inflammatory response lacking evidence of Cryptococcus neoformans, acid-fast staining was negative, serum cryptococcal antigen was positive. Conclusions: Serum cryptococcal antigen has high specificity in cryptococcal pneumonia.

Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are common causes of familial Parkinson's disease (PD). LRRK2 has been shown to bind peroxiredoxin-3 (PRDX3), the most important scavenger of hydrogen peroxide in the mitochondria, in vitro. Here, we examined the interactions of LRRK2 and PRDX3 in Drosophila models by crossing transgenic LRRK2 and PRDX3 flies. As proof of principle experiments, we subsequently challenged LRRK2 and LRRK2/PRDX3 flies with a peroxidase mimic, Ebselen. We demonstrated that co-expression of PRDX3 with the LRRK2 kinase mutant G2019S in bigenic Drosophila ameliorated the G2019S mutant-induced reduction in peroxidase capacity, loss of dopaminergic neurons, shortened lifespan and mitochondrial defects of flight muscles in monogenic flies expressing the G2019S alone. Challenges with Ebselen recapitulated similar rescue of these phenotypic features in mutant-expressing Drosophila. The peroxidase mimic preserved neuronal and mitochondrial and neuronal integrity and improved mobility and survival in mutant-expressing Drosophila. Taken together, our study provides the first in vivo evidence to suggest that phosphoinhibition of endogenous peroxidases could be a mechanism in LRRK2-induced oxidant-mediated neurotoxicity. Our therapeutic experiments also highlight the potential of thiol peroxidases as neuroprotective agents in PD patients carrying LRRK2 mutations.

Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming.

Anaplastic lymphoma kinase (ALK), physiologically expressed only by nervous system cells, displays a remarkable capacity to transform CD4(+) T lymphocytes and other types of nonneural cells. In this study, we report that activity of nucleophosmin (NPM)/ALK chimeric protein, the dominant form of ALK expressed in T cell lymphomas (TCLs), closely resembles cell activation induced by IL-2, the key cytokine supporting growth and survival of normal CD4(+) T lymphocytes. Direct comparison of gene expression by ALK(+) TCL cells treated with an ALK inhibitor and IL-2-dependent ALK(-) TCL cells stimulated with the cytokine revealed a very similar, albeit inverse, gene-regulation pattern. Depending on the analysis method, up to 67% of the affected genes were modulated in common by NPM/ALK and IL-2. Based on the gene expression patterns, Jak/STAT- and IL-2-signaling pathways topped the list of pathways identified as affected by both IL-2 and NPM/ALK. The expression dependence on NPM/ALK and IL-2 of the five selected genes-CD25 (IL-2Rα), Egr-1, Fosl-1, SOCS3, and Irf-4-was confirmed at the protein level. In both ALK(+) TCL and IL-2-stimulated ALK(-) TCL cells, CD25, SOCS3, and Irf-4 genes were activated predominantly by the STAT5 and STAT3 transcription factors, whereas transcription of Egr-1 and Fosl-1 was induced by the MEK-ERK pathway. Finally, we found that Egr-1, a protein not associated previously with either IL-2 or ALK, contributes to the cell proliferation. These findings indicate that NPM/ALK transforms the target CD4(+) T lymphocytes, at least in part, by using the pre-existing, IL-2-dependent signaling pathways.

STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression.

Although STAT5A and STAT5B have some nonredundant functional properties, their distinct contributions to carcinogenesis are not clearly defined. Here we report that STAT5A expression is selectively inhibited by DNA methylation of the STAT5A gene promoter region in cells expressing the oncogenic tyrosine kinase NPM1-ALK (also known as NPM-ALK). The DNA methylation is induced by NPM1-ALK itself via STAT3, and is associated with binding to the promoter of the gene encoding MeCP2 capping protein and with lack of binding of the STAT5A gene transcription activator SP1. Reversal of methylation by the DNA methyltransferase inhibitor 5'-aza-2'-deoxycytidine restores SP1 binding and STAT5A gene expression. Notably, the induced or exogenously expressed STAT5A protein binds to the enhancer and intron 14 of the NPM1-ALK gene and triggers selective suppression of NPM1-ALK expression. These results show that NPM1-ALK induces epigenetic silencing of STAT5A gene and that STAT5A protein can act as a key tumor suppressor by reciprocally inhibiting expression of NPM1-ALK.