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.
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.
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