Training/Research Center-Bone Marrow Failure Syndromes

培训/研究中心-骨髓衰竭综合症

• 批准号: 8658137
• 负责人: Jaroslaw P Maciejewski
• 金额: $ 13.43万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658137
• 关键词: Acquired uniparental disomy; Acute Myelocytic Leukemia; Adopted; Affect; Aplastic Anemia; Area; Biological Assay; Blood Cells; Career Choice; Cell Lineage; Cells; Chromosome abnormality; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clonal Evolution; Commit; Complement; Cytogenetic Analysis; Cytogenetics; DNA; Defect; Detection; Development; Diagnosis; Diagnostic; Discipline; Disease; Dysmyelopoietic Syndromes; Etiology; Evaluation; Evolution; Failure; Fingers; Foundations; Frequencies; Functional disorder; Funding; Future; Gene Mutation; Genes; Genome Scan; Genomics; Goals; Grant; Hematopoiesis; Hematopoietic; Heterogeneity; Immune; Investigation; JAK2 gene; Karyotype determination procedure; Laboratories; Laboratory Study; Lead; Lesion; Loss of Heterozygosity; Maps; Mediating; Metaphase; Methods; Mid-Career Clinical Scientist Award (K24); Molecular; Mutation; Oncogenes; Oncogenic; Outcome; Pancytopenia; Pathogenesis; Patients; Physicians; Play; Principal Investigator; Production; Protocols documentation; Publications; Receptor Protein-Tyrosine Kinases; Recurrence; Research; Research Activity; Research Project Grants; Research Training; Resolution; Risk; Role; Scheme; Scientist; Signal Transduction; Signal Transduction Pathway; Single Nucleotide Polymorphism; Solid; Stem cells; Syndrome; Technology; Time; Training; Training Programs; Translational Research; Treatment Protocols; Tumor Suppressor Proteins; Uniparental Disomy; United States National Institutes of Health; attenuation; base; clinical phenotype; clinically relevant; diagnostic accuracy; experience; improved; interest; mutant; new therapeutic target; novel; post-doctoral training; progenitor; prognostic; programs; receptor; restraint; src-Family Kinases; standard care; tool; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Bone marrow failure (BMF) syndromes, including aplastic anemia (AA) and myelodysplasia (MDS) are disorders characterized by hematopoietic progenitor or stem cell failure resulting in deficient production of one or all blood cell lineages. Immune pathophysiology and propensity for clonal evolution are the unifying factors in these diseases that can be otherwise very heterogenous. Laboratory and clinical studies are needed to better understand the pathophysiology and etiology of MDS and AA with the goal of development of improved diagnostic tools and treatment approaches. In particular our research training program focuses on application of novel molecular technologies to elucidate molecular and immune pathogenesis of bone marrow failure. Research projects which form solid research and clinical foundation of this proposal target diverse topics and include several RO1s. For example, we will investigate chromosomal lesions in bone marrow failure using single nucleotide polymorphism arrays (SNP-A) which as a high resolution karyotyping method allows for the detection of unbalanced DNA defects, including somatic uniparental disomy (UPD) and thereby reveal previously cryptic defects. Detection of such lesions could facilitate identification of novel therapeutic targets, aid diagnosis and improve current prognostic schemes by explaining the phenotypic heterogeneity of MDS. We have demonstrated that somatic UPD is very frequent in MDS and hypothesized that shared regions of UPD may point towards mutations of genes involved in the development of MDS. We mapped invariant UPD and deletions in a large group of patients with MDS and found that UPD11q was particularly frequent in patients with MDS and CMML. Sequencing of this region demonstrated mutations in c-Cbl, an E3 ubiquitin ligase. These research and other related research activities will serve as a basis for continuation of our K24 (BMF) training program which integrates young physician scientists into the clinical and translational research teams and stimulate interest in an academic career path as clinical investigators. Our proposal encompasses a multitargeted approach involving: 1) Systematic evaluation of novel laboratory assays that may improve diagnostic accuracy or understanding of pathophysiologic mechanisms in bone marrow failure; 2) Development of experimental treatment protocols for disease subsets without good treatment options or without a standard treatment approach, 3) Training of post-doctoral fellows to develop clinical trials and translational research projects within the bone marrow failure center, 4) Integration of basic scientists into clinical research and physicians from related disciplines to form productive research teams in the field of bone marrow failure syndromes. The expertise of the principal investigator, together with the experience, size and facilities at CC uniquely fits with the spirit of the K24 award program and would allow Dr. Jaroslaw Maciejewski to commit more time and effort to clinical research and training while continuing creation of a strong research program. NARRATIVE: Myelodysplastic syndromes (MDS) is a heterogeneous group of bone marrow failure states characterized by dysplastic hematopoiesis, deficient blood cell production and a propensity to progression to acute myelogenous leukemia (AML); this heterogeneity has greatly impeded investigations into the molecular pathogenesis and potential therapies for these diseases. We propose that single nucleotide polymorphisms arrays (SNP-A) can be applied, complementary to metaphase cytogenetics for the identification of chromosomal abnormalities, including a newly recognized class of lesion, somatic uniparental disomy. We will precisely map these lesions, identifying genes that may play a role in the disease and potentially act as targets of therapy; these studies will form the basis for the training program proposed.

描述（由申请人提供）：骨髓衰竭（BMF）综合征，包括性障碍性贫血（AA）和骨髓增生性发育不全（MDS）是疾病，其特征是造血细胞衰竭或干细胞衰竭，导致一个或所有血细胞谱系的产生不足。免疫病理生理和克隆进化的倾向是这些疾病中可能非常异体的统一因素。需要实验室和临床研究以更好地了解MDS和AA的病理生理学和病因，以开发改进的诊断工具和治疗方法。特别是我们的研究培训计划的重点是应用新型分子技术来阐明骨髓衰竭的分子和免疫发病机理。构成该提案的可靠研究和临床基础的研究项目针对多种主题，并包括多个RO1。例如，我们将使用单个核苷酸多态性阵列（SNP-A）研究骨髓衰竭中的染色体病变，作为高分辨率核分型方法，该方法允许检测不平衡的DNA缺陷，包括躯体独立疾病（upp），从而揭示了先前神秘的缺陷。通过解释MDS的表型异质性，检测此类病变可以促进鉴定新的治疗靶标，帮助诊断并改善当前的预后方案。我们已经证明，在MDS中，体细胞UPD非常频繁，并假设UPD的共享区域可能指向MDS开发涉及的基因的突变。我们在大量患有MDS的患者中绘制了不变的UPD和删除，发现MDS和CMML患者的UPD11Q特别频繁。该区域的测序表明在C-CBL（E3泛素连接酶）中突变。这些研究和其他相关的研究活动将成为继续我们的K24（BMF）培训计划的基础，该计划将年轻的医师科学家纳入临床和转化研究团队，并激发人们对学术职业道路作为临床研究人员的兴趣。我们的建议涵盖了一种涉及的多武力方法：1）对新型实验室测定的系统评估，这些方法可能会提高骨髓衰竭中对病理生理机制的诊断准确性或理解； 2）制定无需良好治疗选择或没有标准治疗方法的疾病子集的实验治疗方案，3）培训博士后研究员的培训，以开发骨髓失败中心内的临床试验和翻译研究项目，4）基础科学家将基础科学家整合到临床研究中，并从相关学科的医生中融入了相关学科的医生，以形成骨气失败的领域的生产力研究团队。首席研究人员的专业知识，以及CC的经验，规模和设施独特地符合K24奖项计划的精神，并允许Jaroslaw Maciejewski博士将更多的时间和精力用于临床研究和培训，同时继续创建强大的研究计划。 叙事：骨髓增生综合征（MDS）是一组异质的骨髓衰竭状态，其特征是具有发育异常的造血，血细胞的产生不足以及倾向于急性脊髓性白血病（AML）的倾向；这种异质性极大地阻碍了对这些疾病的分子发病机理和潜在疗法的研究。我们提出，可以应用单核苷酸多态性阵列（SNP-A），互补与中期细胞遗传学互补，以鉴定染色体异常，包括新认识的病变类，躯体疾病。我们将精确地绘制这些病变，鉴定可能在该疾病中起作用的基因并有可能充当治疗的靶标。这些研究将构成提出的培训计划的基础。

项目成果

Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders.

• DOI: 10.1038/leu.2012.130
• 发表时间: 2012-12
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Visconte, V.;Makishima, H.;Maciejewski, J. P.;Tiu, R. V.
• 通讯作者: Tiu, R. V.

Paroxysmal nocturnal hemoglobinuria and concurrent JAK2(V617F) mutation.

• DOI: 10.1038/bcj.2012.7
• 发表时间: 2012-03
• 期刊: BLOOD CANCER JOURNAL
• 影响因子: 12.8
• 作者: Sugimori, C.;Padron, E.;Caceres, G.;Shain, K.;Sokol, L.;Zhang, L.;Tiu, R.;O'Keefe, C. L.;Afable, M.;Clemente, M.;Lee, J. M.;Maciejewski, J. P.;List, A. F.;Epling-Burnette, P. K.;Araten, D. J.
• 通讯作者: Araten, D. J.

Cytogenetic and molecular predictors of response in patients with myeloid malignancies without del[5q] treated with lenalidomide.

• DOI: 10.1186/1756-8722-5-4
• 发表时间: 2012-03-05
• 期刊: Journal of hematology & oncology
• 影响因子: 28.5
• 作者: Sugimoto Y;Sekeres MA;Makishima H;Traina F;Visconte V;Jankowska A;Jerez A;Szpurka H;O'Keefe CL;Guinta K;Afable M;Tiu R;McGraw KL;List AF;Maciejewski J
• 通讯作者: Maciejewski J

Clonal hematopoiesis in Philadelphia chromosome-negative bone marrow cells of chronic myeloid leukemia patients receiving dasatinib.

接受达沙替尼治疗的慢性粒细胞白血病患者费城染色体阴性骨髓细胞的克隆造血。

• DOI: 10.1016/j.leukres.2009.08.032
• 发表时间: 2010
• 期刊: Leukemia research
• 影响因子: 2.7
• 作者: Paquette,RonaldL;Nicoll,John;Chalukya,Meenal;Gondek,Lucas;Jasek,Monika;Sawyers,CharlesL;Shah,NeilP;Maciejewski,Jaroslaw
• 通讯作者: Maciejewski,Jaroslaw

The need for additional genetic markers for myelodysplastic syndrome stratification: what does the future hold for prognostication?

• DOI: 10.1586/ehm.12.67
• 发表时间: 2013-02
• 期刊: Expert review of hematology
• 影响因子: 2.8
• 作者: Otrock ZK;Tiu RV;Maciejewski JP;Sekeres MA
• 通讯作者: Sekeres MA