Tracking the fate of the aberrant clone in patients with the Myelodysplastic Syndrome: The influence of treatment on clonal selection and function..

Project Details

Description

TECHNICAL ABSTRACT

Background: Transcriptional regulation of gene expression is controlled at least in part, by mechanisms affecting the methylation of DNA cytidine residues and the acetylation of nucleosomal core histone tails affecting chromatin conformational changes. Transcriptional repression results in dysregulation of critical pathways in primitive hematopoietic stem cells (HSC) in myelodysplastic syndrome (MDS), affecting cytokine/regulatory signaling. This disrupts the normal homeostatic control of HSC proliferation and differentiation and in conjunction with defects in the bone marrow microenvironment, results in accelerated apoptosis, leading to progressive bone marrow failure. Genomic instability of the MDS clone contributes to the development of additional genetic defects, further transcriptional repression and the eventual emergence of increasingly virulent clones. Peripheral blood cytopenias and/or leukemic transformation in up to 40% of patients leads to the high mortality rate associated with the disease. Ablation of the MDS clone to permit re-emergence of presumed residual normal HSC with restoration of bone marrow function has served as the underlying therapeutic rationale. Chemotherapy and allogeneic stem cell transplant represent the most common application of this approach. These strategies have been largely ineffective in permanently eradicating the MDS clone. Little is known about the factors that influence clonal competition, to what degree "normal" HSC may persist, and whether the behavior of the MDS clone can be positively modulated to improve function and delay or prevent emergence of new clones that are associated with disease progression or frank leukemic transformation.

Hypothesis: We hypothesize that agents that target and interfere with different components of the pathogenic pathways can reverse transcriptional repression and improve clinical outcome. We further hypothesize that these agents can modulate the behavior of the MDS HSC ameliorating bone marrow function without eliminating the aberrant clone. Such a strategy could result in reduction in bone marrow failure, thus reducing disease-related morbidity and delaying mortality, and could potentially be delivered with less risk to the patient.

Study Aims: (1) To study clonal competition in MDS, determine the fate of the abnormal clone, and identify factors which may influence its modulation and function. (2) To determine the influence of treatment for MDS on clonal selection by monitoring sequentially the fate of the MDS clone during the course of treatment and during the course of disease evolution and transformation. (3) To study the modulating effect of treatment on apoptosis of HSC progenitors. (4) To determine, using gene array technology, the change in expression of specific genes, including p15 and E-cadherin, and other genes known to be active in the myeloid regulatory pathway. These studies will be made in CD34+ cells from MDS patients and correlated with the change in disease evolution and response to treatment.

Study Design: After obtaining written informed consent, patients who either have MDS and are being entered on a therapeutic clinical trial or those who have early-stage disease and are just being followed will have sequential bone marrow and peripheral blood exams to monitor the behavior and fate of the MDS clone as a function of the natural history of the disease and its treatment.

Relevance: Improved understanding of the factors that affect both the behavior and fate of the MDS clone is critical to developing improved therapeutic strategies.

StatusFinished
Effective start/end date1/01/0431/12/04

Funding

  • U.S. Department of Defense: $1,279,507.00

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