Our research focuses on elucidating the molecular mechanisms whereby menin-mediated epigenetic mechanisms in regulating endocrine cells including pancreatic beta cells, endocrine tumors, and MLL fusion protein-induced leukemia. In particular, we are interested in dissecting the function of menin, which is mutated in hereditary human tumor syndrome, Multiple Endocrine Neoplasia Type 1 (MEN1), in repressing beta cells and endocrine tumors and in promoting leukemogenesis.

1. We seek to elucidate how Menin suppresses endocrine cells, such as pancreatic beta cells, via regulating histone methylations and expression of pro-proliferative genes. We are also interested in identifying menin-regulated key pathways that can be suppressed to inhibit neuroendocrine tumors.

2. Determining how menin, which acts as a tumor promoter in MLL fusion protein-induced leukemia, cooperates with wild-type MLL protein to promote leukemia and how the menin and wt MLL axis can be suppressed to improve therapy for this aggressive leukemia.

3. Understanding how inhibition of menin leads to reversal of established diabetes in mouse models and determining whether the menin pathway could be explored to ameliorate diabetes.

4. Investigating the interplay between menin, post-transcriptional modifications of menin, and TGF-ß signaling in repressing pancreatic beta cells. As both menin and TGF-ß inhibit cell proliferation, we will test whether menin and TGF-ß cooperate to suppress beta cell proliferation and the underlying mechanisms, using biochemical studies and mouse models.

These comprehensive approaches will provide novel insights into the molecular mechanisms for MEN1 tumorigenesis, regulation of beta cells, and leukemogenesis, shedding light on improving therapy against neuroendocrine tumors, leukemia, and diabetes.

The research team of Xianxin Hua, Ph.D., seeks to understand how epigenetic regulations, especially those mediated by menin, control development of a variety of diseases, such as endocrine tumors, leukemia, and diabetes. His group has discovered that menin may act as a scaffold protein or a node to interact with various epigenetic regulators to control expression of genes that modulate cell proliferation and survival. They are elucidating how a cascade of the menin-mediated regulatory step is controlled at the molecular level, using a variety of approaches involving molecular and cell biology, genetics, and mouse models. They seek to help improve the treatment of the diseases by targeting the novel molecular steps.