Conversion of T cells to B cells by inactivation of polycomb-mediated epigenetic suppression of the B-lineage program

12 p.-6 fig.1 tab.Tomokatsu Ikawa, et al.In general, cell fate is determined primarily by transcription factors, followed by epigenetic mechanisms fixing the status. While the importance of transcription factors controlling cell fate has been well characterized, epigenetic regulation of cell fate maintenance remains to be elucidated. Here we provide an obvious fate conversion case, in which the inactivation of polycomb-medicated epigenetic regulation results in conversion of T-lineage progenitors to the B-cell fate. In T-cell-specific Ring1A/B-deficient mice, T-cell development was severely blocked at an immature stage. We found that these developmentally arrested T-cell precursors gave rise to functional B cells upon transfer to immunodeficient mice. We further demonstrated that the arrest was almost completely canceled by additional deletion of Pax5. These results indicate that the maintenance of T-cell fate critically requires epigenetic suppression of the B-lineage gene program.This work was supported in part by grants from the Japan Society for the Promotion of Science (24689042 to T.I.), the Japan Science and Technology Agency (T.I.), RIKEN Center for Integrative Medical Sciences (IMS) Young Chief Investigator program (T.I.), and the Kanae Foundation for the Promotion of Medical Science (T.I.).Peer reviewe

Desensitization treatment with cisplatin after carboplatin hypersensitivity reaction in gynecologic cancer

Platinum-based chemotherapy is the standard regimen for the treatment of gynecologic cancers ; however, hypersensitivity reactions (HR) to platinum often lead to discontinuation of this effective treatment. Here we performed a desensitization protocol for platinum infusion in 3 patients who required platinum re-administration after developing HR. Two patients (Case 1 and 2) were treated with the desensitization protocol successfully without developing HR during the subsequent 3 courses. Case 3 tolerated desensitization well for 2 courses, but in the 3rd course, she developed severe HR immediately after the initiation of cisplatin infusion because the desensitization protocol was unintentionally omitted. These cases show the usefulness and effectiveness of the desensitization protocol for the continuation of platinum treatment in patients who have undergone an extended number of treatments

E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment

The helix-loop-helix protein, E47, is essential for both B- and T-lineage development. Here we demonstrate that in vitro E47 and Notch signaling act in concert to promote T cell development from fetal hematopoieitic progenitors and to restrain development into the natural killer and myeloid cell lineages. The expression of an ensemble of genes associated with Notch signaling is activated by E47, and additionally, Notch signaling and E47 act in parallel pathways to induce a T lineage–specific program of gene expression. Enforced expression of the intracellular domain of Notch rescues the developmental arrest at the T cell commitment stage in E2A-deficient fetal thymocytes. Finally, we demonstrate that regulation of Hes1 expression by Notch signaling and E47 is strikingly similar to that observed during Drosophila melanogaster sensory development. Based on these observations, we propose that in developing fetal thymocytes E47 acts to induce the expression of an ensemble of genes involved in Notch signaling, and that subsequently E47 acts in parallel with Notch signaling to promote T-lineage maturation

Self-regulated left-right asymmetric expression of Pitx2c in the developing mouse limb

AbstractThe transcription factor Pitx2c is expressed in primordial visceral organs in a left-right (L-R) asymmetric manner and executes situs-specific morphogenesis. Here we show that Pitx2c is also L-R asymmetrically expressed in the developing mouse limb. Human PITX2c exhibits the same transcriptional activity in the mouse limb. The asymmetric expression of Pitx2c in the limb also exhibits dorsal-ventral and anterior-posterior polarities, being confined to the posterior-dorsal region of the left limb. Left-sided Pitx2c expression in the limb is regulated by Nodal signaling through a Nodal-responsive enhancer. Pitx2c is expressed in lateral plate mesoderm (LPM)–derived cells in the left limb that contribute to various limb connective tissues. The number of Pitx2c+ cells in the left limb was found to be negatively regulated by Pitx2c itself. Although obvious defects were not apparent in the limb of mice lacking asymmetric Pitx2c expression, Pitx2c may regulate functional L-R asymmetry of the limb

A huge ovarian smooth muscle tumor : a case report

Ovarian smooth muscle tumors are a very rare type of ovarian tumor. In this paper, we report the case of a 62-year-old woman who had a huge smooth muscle tumor of the right ovary. The values of all the serum tumor markers were within normal limit. The tumor measured 25 cm in diameter and weighed 6,200 g. Histological examination revealed that coagulative cellular atypia was modetare to severe, necrosis was not present and mitotic index was low. According to the criteria for the evaluation of the uterine smooth muscle tumors, this huge tumor was diagnosed as atypical leiomyoma. However, we finally made a diagnosis of this tumor as a smooth muscle tumor of uncertain malignant potential (STUMP) because of its huge size. Further information is required regarding the characteristics of ovarian smooth muscle tumor and the propriety to introduce uterine tumor histological criteria to ovarian tumors

Structural and functional insights into IZUMO1 recognition by JUNO in mammalian fertilization

Kato, K., Satouh, Y., Nishimasu, H. et al. Structural and functional insights into IZUMO1 recognition by JUNO in mammalian fertilization. Nat Commun 7, 12198 (2016). https://doi.org/10.1038/ncomms1219

Synthetic studies on pterin glycosides: the first synthesis of 2′-O-(α-d-glucopyranosyl)biopterin

L-Rhamnose was led, in a 14-step-sequence, to N2-(N,N-dimethylaminomethylene)-1′-O-(4-methoxybenzyl)-3-[2-(4-nitrophenyl)ethyl]biopterin (23), an appropriately protected precursor for 2′-O-glycosylation, while 4,6-di-O-acetyl-2,3-di-O-(4-methoxybenzyl)-α-d-glucopyranosyl bromide (32), a novel glycosyl donor, was efficiently prepared from d-glucose in 8 steps. The first synthesis of 2′-O-(α-d-glucopyranosyl)biopterin (2a) was achieved by treatment of the key intermediate 23 with 32 in the presence of silver triflate and tetramethylurea, followed by successive removal of the protecting groups