Acquired mutations of JAK2 and TET2 are frequent in myeloproliferative neoplasms (MPNs). We examined the individual and cooperative effects of these mutations on MPN development. Recipients of ...JAK2V617F cells developed primary myelofibrosis–like features; the addition of loss of TET2 worsened this JAK2V617F-induced disease, causing prolonged leukocytosis, splenomegaly, extramedullary hematopoiesis, and modestly shorter survival. Double-mutant (JAK2V617F plus loss of TET2) myeloid cells were more likely to be in a proliferative state than JAK2V617F single-mutant myeloid cells. In a serial competitive transplantation assay, JAK2V617F cells resulted in decreased chimerism in the second recipients, which did not develop MPNs. In marked contrast, cooperation between JAK2V617F and loss of TET2 developed and maintained MPNs in the second recipients by compensating for impaired hematopoietic stem cell (HSC) functioning. In-vitro sequential colony formation assays also supported the observation that JAK2V617F did not maintain HSC functioning over the long-term, but concurrent loss of TET2 mutation restored it. Transcriptional profiling revealed that loss of TET2 affected the expression of many HSC signature genes. We conclude that loss of TET2 has two different roles in MPNs: disease accelerator and disease initiator and sustainer in combination with JAK2V617F.
•Loss of TET2 accelerates the degree of malignancy of MPNs in combination with JAK2V617F.•Loss of TET2 sustains MPNs in combination with JAK2V617F.
TET2 mutation in diffuse large B-cell lymphoma Kubuki, Yoko; Yamaji, Takumi; Hidaka, Tomonori ...
Journal of Clinical and Experimental Hematopathology,
2017, Volume:
56, Issue:
3
Journal Article
Peer reviewed
Open access
Ten-eleven translocation-2 (TET2) mutation is frequently observed in myeloid malignancies, and loss-of-function of TET2 is essential for the initiation of malignant hematopoiesis. TET2 mutation ...presents across disease entities and was reported in lymphoid malignancies. We investigated TET2 mutations in 27 diffuse large B-cell lymphoma (DLBCL) patients and found a frameshift mutation in 1 case (3.7%). TET2 mutation occurred in some populations of DLBCL patients and was likely involved in the pathogenesis of their malignancies.
The patient was a 63-year-old man. He was examined by a local doctor for dyspnea, where he was administered oral steroids and started on inhalation therapy for a diagnosis of bronchial asthma. ...However, his symptoms worsened and he was brought to our hospital. On admission, he was diagnosed with atrial fibrillation and acute heart failure. Upon administration of anticoagulants to prevent embolism in this patient with atrial fibrillation, the patient developed bloody stool. Colonoscopy revealed multiple diverticula in the hepatic flexure, along with ulcers and white coating localized to that area. Diverticular colitis was initially suspected, but vegetative amoebas were found in a tissue biopsy of the ulcers and he was diagnosed with amebic colitis. The ulcers healed with administration of metronidazole. We report this case in which amebic colitis developed in a man with asymptomatic Entamoeba histolytica infection from the use of steroids and anticoagulants, with the lesions localized in the area with multiple colon diverticula.
TET2 Mutation in Adult T-Cell Leukemia/Lymphoma Shimoda, Kazuya; Shide, Kotaro; Kameda, Takuro ...
Journal of Clinical and Experimental Hematopathology,
2015, Volume:
55, Issue:
3
Journal Article
Peer reviewed
Open access
Loss-of-function of ten-eleven translocation-2 (TET2) is a common event in myeloid malignancies, and plays pleiotropic roles, including augmenting stem cell self-renewal and skewing hematopoietic ...cells to the myeloid lineage. TET2 mutation has also been reported in lymphoid malignancies; 5.7～12% of diffuse large B-cell lymphomas and 18～83% of angioimmunoblastic T-cell lymphomas had TET2 mutations. We investigated TET2 mutations in 22 adult T-cell leukemia/lymphoma (ATLL) patients and identified a missense mutation in 3 cases (14%). TET2 mutation occurred in a number of ATLL patients and was likely involved in their leukemogenesis. J Clin Exp Hematop 55(3) : 145-149, 2015
Dear Editor, Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) that primarily involves the megakaryocytic lineage, and is characterized by increased numbers of large, mature ...megakaryocytes in bone marrow as well as sustained thrombocytosis. Mutations in JAK2 or calreticulin (CALR) are present in about 50% and 25% of patients with ET, respectively, and these mutations are thought to drive MPN 1. CALR and JAK2 mutations are mutually exclusive in MPNs 1. Compared with patients with JAK2-mutated ET, patients with CALR-mutated ET have lower Hb levels and lower numbers of granulocytes, but higher numbers of platelets 2-6. The CALR-mutated patients also have a lower incidence of thrombosis during their clinical course. Genetic background such as race may influence the risk of thrombosis, and recent study reported that Japanese ET patients with JAK2 mutation had a higher cumulative incidence of thrombosis than those with CALR mutations, although the differences were not significant 6. Therefore, we analyzed the impact of JAK2 and CALR mutations on clinical features and thrombotic events in Japanese patients with ET. KCI Citation Count: 0
Background and Aim. It is difficult to master the skill of discriminating gastric adenoma from early gastric cancer by conventional endoscopy or magnifying endoscopy combined with narrow-band ...imaging, because the colors and morphologies of these neoplasms are occasionally similar. We focused on the surrounding gastric mucosa findings in order to determine how to discriminate between early gastric cancer and gastric adenoma by analyzing the characteristics of the gastric background mucosa. Methods. We retrospectively examined 146 patients who underwent endoscopic submucosal dissection for gastric neoplasm between October 2009 and January 2015. The boundary of atrophic gastritis was classified endoscopically according to the Kimura-Takemoto classification system. Of 146 lesions, 63 early gastric cancers and 21 gastric adenomas were ultimately evaluated and assessed. Results. Almost all gastric adenomas were accompanied by open-type gastritis, whereas 47 and 16 early gastric cancers were accompanied by open-type and closed-type gastritis, respectively (p = 0.037). Conclusions. The evaluation of the boundary of atrophic gastritis associated with gastric neoplasms appears to be useful for discrimination between early gastric cancer and gastric adenoma. When gastric neoplasm is present in the context of surrounding localized gastric atrophy, gastric cancer is probable but not certain.
TET2 Mutation in Adult T-Cell Leukemia/Lymphoma Kazuya Shimoda; Kotaro Shide; Takuro Kameda ...
Journal of Clinical and Experimental Hematopathology,
12/2015, Volume:
55, Issue:
3
Journal Article
Peer reviewed
Loss-of-function of ten-eleven translocation-2 (TET2) is a common event in myeloid malignancies, and plays pleiotropic roles, including augmenting stem cell self-renewal and skewing hematopoietic ...cells to the myeloid lineage. TET2 mutation has also been reported in lymphoid malignancies; 5.7-12% of diffuse large B-cell lymphomas and 18-83% of angioimmunoblastic T-cell lymphomas had TET2 mutations. We investigated TET2 mutations in 22 adult T-cell leukemia/lymphoma (ATLL) patients and identified a missense mutation in 3 cases (14%). TET2 mutation occurred in a number of ATLL patients and was likely involved in their leukemogenesis.
Myeloproliferative neoplasms (MPNs) are clinically characterized by the chronic overproduction of differentiated peripheral blood cells and the gradual expansion of malignant ...intramedullary/extramedullary hematopoiesis. In MPNs mutations in JAK2 MPL or CALR are detected mutually exclusive in more than 90% of cases 1,2. Mutations in them lead to the abnormal activation of JAK/STAT signaling and the autonomous growth of differentiated cells therefore they are considered as “driver” gene mutations. In addition to the above driver gene mutations mutations in epigenetic regulators such as TET2 DNMT3A ASXL1 EZH2 or IDH1/2 are detected in about 5%–30% of cases respectively 3. Mutations in TET2 DNMT3A EZH2 or IDH1/2 commonly confer the increased self-renewal capacity on normal hematopoietic stem cells (HSCs) but they do not lead to the autonomous growth of differentiated cells and only exhibit subtle clinical phenotypes 4,6–8,5. It was unclear how mutations in such epigenetic regulators influenced abnormal HSCs with driver gene mutations how they influenced the disease phenotype or whether a single driver gene mutation was sufficient for the initiation of human MPNs. Therefore we focused on JAK2V617F and loss of TET2—the former as a representative of driver gene mutations and the latter as a representative of mutations in epigenetic regulators—and examined the influence of single or double mutations on HSCs (Lineage−Sca-1+c-Kit+ cells (LSKs)) by functional analyses and microarray whole-genome expression analyses 9. Gene expression profiling showed that the HSC fingerprint genes 10 was statistically equally enriched in TET2-knockdown-LSKs but negatively enriched in JAK2V617F–LSKs compared to that in wild-type-LSKs. Double-mutant-LSKs showed the same tendency as JAK2V617F–LSKs in terms of their HSC fingerprint genes but the expression of individual genes differed between the two groups. Among 245 HSC fingerprint genes 100 were more highly expressed in double-mutant-LSKs than in JAK2V617F–LSKs. These altered gene expressions might partly explain the mechanisms of initiation and progression of MPNs which was observed in the functional analyses 9. Here we describe gene expression profiles deposited at the Gene Expression Omnibus (GEO) under the accession number GSE62302 including experimental methods and quality control analyses.
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