The goal of this proposal is to define the role of high mobility group A (HMGA) chromatin remodeling proteins in tumor progression in myeloproliferative neoplasms (MPN). MPN are a heterogeneous group of acquired, clonal hematopoietic stem and progenitor cell disorders characterized by overproduction of mature blood cells and a propensity for leukemic transformation, although the molecular mechanisms for tumor progression are unknown. Polycythemia vera (PV) is the prototypical MPN defined by acquired activating mutations in the gene encoding JAK2, the obligate tyrosine kinase of hematopoietic growth factor receptors for erythropoietin, G-CSF, and thrombopoietin, resulting in uncontrolled production of red cells, white cells, and platelets. JAK2 mutations alone, however, do not account for progression from chronic, indolent PV to acute leukemia. Importantly, outcomes for PV patients who progress to leukemia are abysmal; thus, research is needed to determine how this occurs. Our scientific premise is based on compelling preliminary data indicating that PV tumor progression is associated with overexpression in genes encoding the HMGA chromatin binding proteins. HMGA proteins modulate gene expression by remodeling chromatin and recruiting transcription factor complexes to DNA. Our group was the first to discover that HMGA genes function as potent oncogenes that drive leukemic transformation in cultured cell models and transgenic mice. Moreover, HMGA overexpression portends adverse clinical outcomes in diverse hematologic malignancies and solid tumors. In diverse tumor models, we found that HMGA1 drives tumor progression through epigenetic alterations that induce stem cell transcriptional networks. In preliminary data from ChIP-Seq in human CD34+ stem and progenitor cells, we found that HMGA1 occupies promoter-enhancer regions for genes involved in self-renewal, de- differentiation, inflammation, and myeloid leukemia. These exciting findings led us to the following hypotheses: 1) HMGA proteins are critical drivers of tumor progression in PV by inducing transcriptional networks that maintain uncontrolled self-renewal, de-differentiation, and leukemic transformation, and, 2) Targeting HMGA pathways will block tumor progression and reprogram advanced disease to a more indolent phenotype. We have >600 primary human MPN tumors with detailed clinical annotation and genomic data and we generated innovative mouse models to study HMGA in PV progression. Here, we propose to harness our unique models, tumor samples, and expertise to elucidate the role of HMGA chromatin regulators in PV progression with the following Specific Aims: 1) To determine whether HMGA overexpression predicts tumor progression and to define cooperating genomic lesions and molecular mechanisms, 2) To define the functional significance of HMGA in tumor progression in vivo using mouse models, and, 3) To investigate the clinical efficacy of targeting HMGA pathways. Our work should uncover novel mechanisms driving disease progression and open the door to new therapeutic strategies for MPN and possibly other myeloid malignancies.

Public Health Relevance

Myeloproliferative neoplasms (MPN) are tumors affecting blood stem cells, which are associated with an increased risk for transformation to aggressive blood cancers called leukemia. The causes for disease progression to leukemia remain obscure and treatment outcomes for these patients are abysmal. Here, we propose studies to determine why some patients develop leukemia so that better therapies, or even preventative strategies, can be developed.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Yang, Yu-Chung
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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