Thank YOU, 1-eye and others, for all the great information. All the SCIENCE and SCIENTIST are REAL. Those who bash are here for different reasons. As always, I believe those of us that hold and add will laugh all the way to the BANK. $RGBP$ $BMSN$ $ENTB$
RGBP Launch is Coming $oon,, as FDA News is Due Out the Week of Dec 8th! ;-)
BMSN owns 58% of RGBP! ;-)
....soOOoo Many Investors want in and arRre gonna Miss OUT because of GREED of trying to Buy in Lower! :-( SHORTING FEES arRre Adding UP for them!! :-(
Cover $urge $oon!! ;-)
...followed by a LOT of Cha$ers Run'n UP da PPS of RGBP & BMSN!! ;-)
HarRr dee HarRr HarRr! ;-)
The Conferance is going on $oon... & a PPS ALWAYS Pops During and After a Conference!! ;-) ...and this will be good for RGBP, BMSN, & ENTB!! ;-) ~~~MANY DRs find out about RGBP~BMSN~ENTB for da 1st time and they INVE$T!! ;-) --- http://ash.confex.com/ash/2014/webprogram/Paper74085.html
56th ASH Annual Meeting & Exposition =
The premier event in malignant & non-malignant hematology
December 6-9, 2014 Moscone Center, San Francisco, CA
1337 NR2F6 (EAR-2) Is a Novel Leukemia Oncogene Whose Cellular Function Is to Regulate Terminal Differentiation of Erythrocytes at the Proerythroblast Stage.
Program: Oral and Poster Abstracts
Session: 101. Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron: Poster I Saturday, December 6, 2014, 5:30 PM-7:30 PM West Building, Level 1 (Moscone Center)
Christine Victoria Ichim, PhD1*, Dzana Dervovic, PhD2*, David Koos, PhD1 *, Marciano D. Reis, MD3, Alden Chesney, MD, FRCPC4* and Richard A. Wells, MD, DPhil3,5
1Regen BioPharma, San Diego, CA
2University of Toronto, Toronto, ON, Canada
3Sunnybrook Health Sciences Centre, Toronto, ON, Canada
4Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, ON, Canada
5Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Canada
The leukemia stem cell model suggests that elucidation of the genes that regulate growth ability within the leukemia cell hierarchy will have important clinical relevance. We showed that the expression of NR2F6 (EAR-2), is greater in clonogenic leukemia single cells than in leukemia cells that do not divide, and that this gene is over-expressed in patients with acute myeloid leukemia and myelodysplastic syndrome. In vivo, overexpression of EAR-2 using a retroviral vector in a chimeric mouse model leads to a condition that resembles myelodysplastic syndrome with hypercellular bone marrow, increased blasts, abnormal localization of immature progenitors, morphological dysplasia of the erythroid lineage and a competitive advantage over wild-type cells, that eventually leads to AML in a subset of the mice, or after secondary-transplantation. Interestingly, animals transplanted with bone marrow that over-expresses EAR-2 develop leukemia that is preceded by expansion of the stem cell compartment in the transplanted mice—suggesting that EAR-2 is an important regulator of hematopoietic stem cell differentiation. Here we report that over-expression of EAR-2 also has a profound effect on the differentiation of erythroid progenitor cells both in vitro and in vivo. Studies of the roles of EAR-2 in normal primary bone marrow cells in vitro showed that overexpression of EAR-2 profoundly impaired differentiation along the erythroid lineage. EAR-2 over-expressing bone marrow cells formed 40% fewer BFU-E colonies, but had greatly extended replating capacity in colony assays. While knockdown of EAR-2 increased the number of cells produced per BFU-E colony 300%. Normal mice transplanted with grafts of purified bone marrow cells that over-expressed EAR-2 developed a rapidly fatal leukemia characterized by pancytopenia, enlargement of the spleen, and infiltration of blasts into the spleen, liver and peripheral blood. Sick animals had profound reduction of peripheral blood cell counts, particularly anemia with a 55% reduction in hemoglobin levels. Anemia was evident even on gross inspection of the blood and the liver in EAR-2 overexpressing animals Analysis of the leukemic cells revealed an erythroblastic morphology, with the immunophenotype lineageneg, CD71high, TER119med. Hence, we wondered weather EAR-2 caused leukemia by arresting erythroid progenitor cell differentiation. Examination of the bone marrow of pre-leukemic animals showed a four-fold increase in cells with a pro-erythroblastic immunophenotype (CD71highTER119med , region I), and a four-fold decrease in orthochromatophilic erythroblasts (CD71lowTER119high , region IV). We observed no change in the numbers of basophilic erythroblasts (CD71highTER119high , region II) or late basophilic and polychromatophilic erythroblasts (CD71medTER119high, region III). These data suggests that over-expression of EAR-2 blocks erythroid cell differentiation at the pro-erythroblastic stage. Since EAR-2 over-expressing recipients died within 4 week, we wanted to definitively test whether animals had compromised radioprotection. We showed that decreasing the size of the bone marrow graft, reduced survival of the EAR-2 over-expressing cohort by a week, but had no effect on control animals proving that EAR-2 over-expression has a profound effect on erythropoietic reconstitution in vivo. Mechanistically, we show that DNA binding is necessary for EAR-2 function, and that EAR-2 functions in an HDAC-dependent manner, regulating expression of several genes. Pre-leukemic pro-erythroblastic cells (CD71highTER119med) that over-expressed EAR-2 had lower expression of genes involved in erythroid differentiation such as GATA1, EBF1, inhibitor of NFKB (NFKBia), ETV6, CEBP/a, LMO2, and Nfe2, and increased expression of GATA2, GLI1, ID1 and PU.1 than GFP control pro-erythroblasts. These data establish that EAR-2 is a novel oncogene whose cellular function is to regulate terminal differentiation of erythroid cells at the proerythroblastic (CD71highTER119med) stage by deregulating gene expression necessary for erythroid differentiation.
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