ABSTRACT
Phosphorylated signal transducer and activator of transcription 5 (STAT5) is a biomarker and potential molecular target for hematologic malignancies. We have shown previously that lethal myeloproliferative disease (MPD) in mice mediated by persistently activated STAT5 (STAT5a(S711F)) requires the N-domain, but the mechanism was not defined. We now demonstrate by retrovirally complementing STAT5ab(null/null) primary mast cells that relative to wild-type STAT5a, STAT5a lacking the N-domain (STAT5aDeltaN) ineffectively protected against cytokine withdrawal-induced cell death. Both STAT5a and STAT5aDeltaN bound to a site in the bcl-2 gene and both bound near the microRNA 15b/16 cluster. However, only STAT5a could effectively induce bcl-2 mRNA and reciprocally suppress miR15b/16 leading to maintained bcl-2 protein levels. After retroviral complementation of STAT5ab(null/null) fetal liver cells and transplantation, persistently active STAT5a(S711F) lacking the N-domain (STAT5aDeltaN(S711F)) was insufficient to protect c-Kit(+)Lin(-)Sca-1(+) (KLS) cells from apoptosis and unable to induce bcl-2 expression, whereas STAT5a(S711F) caused robust KLS cell expansion, induction of bcl-2, and lethal MPD. Severe attenuation of MPD by STAT5aDeltaN(S711F) was reversed by H2k/bcl-2 transgenic expression. Overall, these studies define N-domain-dependent survival signaling as an Achilles heel of persistent STAT5 activation and highlight the potential therapeutic importance of targeting STAT5 N-domain-mediated regulation of bcl-2 family members.
Subject(s)
MicroRNAs/metabolism , Myeloproliferative Disorders/physiopathology , Proto-Oncogene Proteins c-bcl-2/genetics , STAT5 Transcription Factor/genetics , Animals , Cell Survival/physiology , Gene Expression Regulation, Neoplastic , Hematopoietic Stem Cells/pathology , Hematopoietic Stem Cells/physiology , Introns/physiology , Membrane Proteins/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Morphinans/metabolism , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/pathology , Protein Structure, Tertiary , RNA Processing, Post-Transcriptional/physiology , STAT5 Transcription Factor/chemistry , STAT5 Transcription Factor/metabolism , Signal Transduction/physiologyABSTRACT
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. GIST have characteristic morphological features and are positive for KIT (CD117). Overexpression of KIT in the tumor cells results from constitutive activation of the KIT tyrosine kinase receptor. KIT activation leads to intracellular signaling that causes increased cellular proliferation and enhanced cell survival leading to tumor formation. A successful therapeutic strategy is available with the pharmacological agent SCI.-571 that blocks the intracellular effects of KIT activation. GIST are more common in the stomach (60-70%) and the small intestine (25-35%), with a minority of lesions occurring in the colon, rectum, appendix and esophagus. GIST differ histologically, immunohistochemically and genetically from leiomyomas, leiomyosarcomas and schwannomas. The pathologist plays an important role in the evaluation of these lesions. Adequate gross and microscopic pathological evaluation are crucial in the determination of treatment and prognosis.
Subject(s)
Gastrointestinal Neoplasms/pathology , Stromal Cells/pathology , Biomarkers, Tumor , Biopsy, Needle , Gastrointestinal Neoplasms/diagnostic imaging , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/metabolism , Humans , Immunohistochemistry , Prognosis , Proto-Oncogene Proteins c-kit/metabolism , Stromal Cells/metabolism , UltrasonographySubject(s)
Aortic Aneurysm/diagnosis , Aortic Dissection/diagnosis , Chest Pain/etiology , Aortic Dissection/complications , Aortic Aneurysm/complications , Blood Chemical Analysis , Crack Cocaine , Diagnosis, Differential , Electrocardiography , Humans , Male , Middle Aged , Tomography, X-Ray ComputedABSTRACT
Choledochal cyst is a rare congenital anomaly of the biliary system that may be associated with other abnormalities of the hepatobiliary tract. We report a case of an 11-year-old boy in whom the preoperative evaluation revealed a choledochal cyst and intraoperative cholangiopancreatography showed a cystic mass in the pancreas. Examination of the choledocho-pancreatico-duodenectomy specimen showed a multilocular cyst in the pancreas in addition to a segmental dilation of the common bile duct. The findings in our case adds pancreatic cyst to the spectrum of abnormalities associated with choledochal cyst and may also support the theory that choledochal cyst is the predominant abnormality in a widespread spectrum of the pancreatobiliary duct dysplasia.
