Mutation-mediated Pathogens of Myeloid Malignancies
The role of HoxBlinc INCRA in NPM1 mutation-mediated pathogens of myeloid malignancies
PIs: Suming Huang, PhD (University of Florida), Mingjiang Xu, MD, PhD (University of Miami Sylvester Caner Center)
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Nucleophosmin (NPM1) is one of the most frequently mutated genes in acute myeloid leukemia. NPM1 mutation results in a signature aberrant up-regulation of HOX genes. Ectopic activation of HOX gene is critical for the pathogenesis of the NPM1-mutation mediated myeloid malignancies. However, it remains to be determined how NPM1 mutation activates HOX genes to perturb hematopoietic stem/ progenitor cell (HSC/HPC) function and leading acute myeloid leukemia. We discovered a long intergenic non-coding RNA, HoxBlinc, which is specifically activated in the NPM1-mutated AML patients and its expression resulted in an up-regulation of several HOX genes. Downregulation of HoxBlinc RNA in the NPM1-mutated AML cells led to a block in leukemic cell proliferation and increased apoptosis. In this proposal we will investigate if NPM1 mutation leads to activation of HoxBlinc lincRNA in AML and how expression of HoxBlinc lincRNA alters chromatin structure, HOX gene expression, and HSC/HPC property that eventually leading to pathogenesis of NPM1-mutated AML. We anticipate that the proposed research will lead to better understanding of pathogenesis of NPM1 mutation mediated AML and prediction of the prognosis and therapy of NPM1-mutated myeloid malignancies.
Dr. Xu has expertise in hematopoietic stem cell biology, hematological malignancies as well as modeling and evaluating mouse models of hematologic diseases. (Zhao Z et al. Cell reports 2015; Li Z et al. Blood 2011; Wang J et al. Blood 2014). Dr. Huang has expertise in chromatin insulator and epigenetic regulation of hematopoiesis. The Huang lab has established RNA-seq, ChIP-seq, MNase-seq and 4C protocols and used these assays regularly (Deng C et al. Cell reports 2016; Li Y et al. Nucleic Acids Res 2016; Patel B et al. Leukemia 2014). Therefore, Dr. Xu’s team will focused on the role of these Hox gene associated eRNAs in the biology of HSC/HPC both in vitro and in animal models, while Dr. Huang will be studying the underlying molecular mechanisms by analyzing the chromatin structure using whole genome profiling approaches. Clearly, both investigators are essential and will play crucial roles for the success of the proposed studies. The combined expertise of the two investigators is necessary in making significant strides towards our understanding of the role of Hox gene associated lincRNAs in normal and malignant hematopoiesis in a timely and efficient fashion.