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Yang Lab

Epigenetic regulation in normal hematopoiesis and myeloid malignancies

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Investigator / Contact Person Feng-Chun Yang

Research

Myeloid malignancies are a broad class of blood disorders, including myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and acute myeloid leukemia (AML). In the past several years, numerous novel genetic lesions have been identified in patients with myeloid malignancies, which dramatically improved our understanding of the molecular basis of these diseases. However, an ultra-critical and challenging scientific question remains in the field of myeloid malignancies, which is to determine the role of each of these novel genetic lesions in the multistep pathogenesis of myeloid malignancies and to clarify their underlining cellular and molecular mechanisms. The major goal of his laboratory is to elucidate the cellular and molecular mechanism of myeloid malignancies by investigating the effects of alterations in ASXL family genes, NF1, and BAP1 inactivation on the pathogenesis of myeloid malignancies utilizing both primary patient specimens and state of the art gene-modified mouse models.

ASXL genes are mutated/deleted with high frequencies in a variety of myeloid malignancies including MDS/MPN, MDS, and AML, and its alterations are associated with poor prognosis. These findings indicate that alterations of ASXL family genes might represent an important event in the pathogenesis of myeloid malignancies. We have established several mouse models of ASXL1/2/3. These animal models provide unique platforms for exploring the impact of Asxl family gene mutations on hematopoiesis in vivo. These models also allow us to decipher the role of ASXL family genes in normal hematopoiesis and their mutations in the pathogenesis of myeloid malignancies utilizing both primary patient specimens and state of the art gene-modified mouse models. Asxl1 mutations frequently co-occur with other gene mutations in myeloid malignancies, including NF1, RAS, JAK2, TET2, and RUNX1. They are also investigating whether Nf1 haploinsufficiency or JAK2V617F co-operates with Asxl1 haploinsufficiency to promote the development/ transformation of myeloid malignancies in vivo. Their long-term goal is to identify novel therapeutic targets and to develop rational therapies to treat myeloid malignancies.