Identifying the molecular basis for hormonal influence on hematopoiesis

确定激素影响造血的分子基础

• 批准号: 8501441
• 负责人: Aparna Vasanthakumar
• 金额: $ 5.77万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501441
• 关键词: Acetylation; Adult; Androgens; Animal Model; Animals; Aplastic Anemia; B-Lymphocytes; Biological Assay; Blood; Blood Cells; Bone Marrow; Cancer Patient; Cell Count; Cell physiology; Cells; Chromatin Structure; Clinical; Commit; DNA; DNA Methylation; DNA Methyltransferase; DNA Methyltransferase 3B; DNA Modification Methylases; Defect; Development; Dyskeratosis Congenita; Embryo; Embryonic Development; Employee Strikes; Engraftment; Environment; Enzymes; Epigenetic Process; Estrogens; Excision; Failure; Female; Fetal Liver; Future; Gender; Gene Deletion; Gene Expression; Gene Mutation; Genes; Gonadal Steroid Hormones; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hepatocyte; Histone H3; Histones; Homing; Hormonal; Hormones; Human; Immune; In Vitro; Laboratories; Lead; Lymphopenia; Maintenance; Malignant Neoplasms; Marrow; Measures; Mediastinal; Methylation; Mitotic Activity; Modification; Molecular; Multipotent Stem Cells; Mus; Myeloid Cells; Ovariectomy; Pancytopenia; Patients; Pattern; Persons; Physiology; Production; Protein Isoforms; Proteins; Recovery; Research; Source; Stem cell transplant; Stem cells; Steroids; Syndrome; Testing; Time; Transgenic Mice; Transplant Recipients; Transplantation; Umbilical cord structure; Work; base; cancer cell; chemotherapy; craniofacial; experience; histone modification; human cord blood CD34+ cell; immunodeficiency-centromeric instability-facial anomalies syndrome; insight; male; methyl group; mouse model; novel; peripheral blood; pluripotency; progenitor; reconstitution; self-renewal; sex; stem; stem cell differentiation; tumor; tumorigenesis

DESCRIPTION (provided by applicant): It has been known for a long time that the hormonal environment of a person influences bone marrow function. However, the precise molecular mechanism by which this occurs is not known. Epigenetic changes, such as the attachment of a methyl group to DNA and the alteration of histone proteins can regulate the expression of genes that are necessary for stem cell differentiation. This proposal utilizes an animal model that expresses DNMT3B7, a truncated DNA methyltransferase 3B isoform that is commonly expressed in human cancers, to interrogate whether DNA methylation changes can influence the development of blood cells. To test the influence of DNMT3B7 expression on blood cell development, DNMT3B7-expressing fetal liver cells or wild-type E14.5 fetal liver cells were transplanted into recipient animals. Interestingly, female recipients failed to achieve normal peripheral blood counts in the first two months after undergoing transplantation with DNMT3B7-expressing cells, but male recipients had normal blood counts. Transplantation into females that lacked female hormones demonstrated loss of the observed effect, suggesting that the female hormonal milieu is suppressive to DNMT3B7-expressing stem cell function. Thus, we have found that DNMT3B7 expression uncovers a striking influence of gender i.e., hormonal milieu, on stem cell function. I hypothesize that the expression of DNMT3B7 renders HSCs more sensitive to the hormonal milieu in female mice by altering DNA methylation patterns, and thus the expression of genes associated with HSC self- renewal and differentiation. I will use three specific aims to test my hypothesis: (1) Test the impact of DNMT3B7 expression on hematopoietic stem and progenitor cells regarding (a) induced epigenetic changes and (b) their in vitro colony forming potential in the presence and absence of sex-specific hormones; (2) Measure the influence of sex hormones on the homing of HSCs to the bone marrow; (3) Examine the mechanism by which DNMT3B7 expression renders HSCs responsive to female hormones. The proposed work will give us more insight into the mechanisms that promote HSC engraftment and reconstitution in the presence of sex-specific hormones and therefore could have a significant impact on clinical stem cell transplantation.

描述（由申请人提供）：长期以来，人们都知道一个人的激素环境会影响骨髓功能。然而，这种情况发生的精确分子机制尚不清楚。表观遗传变化，如甲基基团与DNA的连接和组蛋白的改变可以调节干细胞分化所必需的基因的表达。该提案利用表达DNMT 3B 7的动物模型，DNMT 3B 7是一种通常在人类癌症中表达的截短的DNA甲基转移酶3B同种型，以询问DNA甲基化变化是否会影响血细胞的发育。为了测试DNMT 3B 7表达对血细胞发育的影响，将表达DNMT 3B 7的胎肝细胞或野生型E14.5胎肝细胞移植到受体动物中。有趣的是，女性受者在接受DNMT 3B 7表达细胞移植后的前两个月内未能达到正常的外周血细胞计数，但男性受者的血细胞计数正常。移植到缺乏雌性激素的雌性动物中表现出所观察到的效果的丧失，表明雌性激素环境对表达DNMT 3B 7的干细胞功能具有抑制作用。因此，我们发现DNMT 3B 7表达揭示了性别的显著影响，即，激素环境对干细胞功能的影响 我推测DNMT 3B 7的表达通过改变DNA甲基化模式，从而改变与HSC自我更新和分化相关的基因的表达，使HSC对雌性小鼠中的激素环境更敏感。我将使用三个具体的目的来验证我的假设：（1）测试DNMT 3B 7表达对造血干细胞和祖细胞的影响，包括（a）诱导的表观遗传变化和（B）在存在和不存在性别特异性激素的情况下它们的体外集落形成潜力;（2）测量性激素对HSC向骨髓归巢的影响;（3）研究DNMT 3B 7表达使HSC对雌性激素应答的机制。 拟议的工作将使我们更深入地了解在性别特异性激素存在下促进HSC植入和重建的机制，因此可能对临床干细胞移植产生重大影响。

项目成果

2-Hydroxyglutarate in IDH mutant acute myeloid leukemia: predicting patient responses, minimal residual disease and correlations with methylcytosine and hydroxymethylcytosine levels.

IDH 突变型急性髓系白血病中的 2-羟基戊二酸：预测患者反应、微小残留病以及与甲基胞嘧啶和羟甲基胞嘧啶水平的相关性。

• DOI: 10.3109/10428194.2012.701009
• 发表时间: 2013
• 期刊: Leukemia & lymphoma
• 影响因子: 2.6
• 作者: Pollyea,DanielA;Kohrt,HolbrookE;Zhang,Bing;Zehnder,James;Schenkein,David;Fantin,Valeria;Straley,Kimberly;Vasanthakumar,Aparna;Abdel-Wahab,Omar;Levine,Ross;Godley,LucyA;Medeiros,BrunoC
• 通讯作者: Medeiros,BrunoC