The research interests of the Rual lab lie in the field of cancer systems biology and the use of proteomic approaches to study cellular networks. We focus on the systematic analysis of protein interactions in biological systems and their relationship to human disease, with particular interest in the MLL/HOXA9 axis as well as the Hedgehog and the Notch pathways.
CHARACTERIZATION OF THE MLL AND HOXA9-REGULATED ENHANCEOSOME MOLECULAR NETWORKS IN ACUTE LEUKEMIA
As part of a complex ensemble of hematopoietic regulators, MLL and HOXA9 help maintain the balance between hematopoietic stem/progenitor cell (HSPC) self-renewal and myeloid/lymphoid cell differentiation in the bone marrow. Several genetic mutations observed in acute myeloid leukemia (AML) patients, e.g., MLL rearrangements, are associated with aberrant upregulation of HOXA9, thus disrupting the hematopoietic balance towards leukemogenesis. Systematic characterization of the molecular interactions in which HOXA9 and MLL/HOXA9-axis proteins are involved should shed light on the mechanisms that govern these proteins during both normal hematopoiesis and leukemogenesis. In collaboration with the Hess lab, we are generating a comprehensive map of the MLL/HOXA9 molecular networks by taking advantage of our protein-protein interaction mapping platform, which combines the use of two complementary, high-throughput technologies, i.e., affinity purification coupled to mass spectrometry analysis (AP-MS) and the yeast two-hybrid system (Y2H). Our projects on the MLL/HOXA9 axis are sponsored by the National Cancer Institute (NCI) of the National Institutes of Health (NIH). Previous funding supports for these projects also include the When Everyone Survives (WES) foundation and the American Society of Hematology (ASH).
CHARACTERIZATION OF THE NOTCH AND HEDGEHOG MOLECULAR NETWORKS IN BRAIN TUMORS
How does the ensemble of protein interactions govern biological processes in the cell and how can disruptions of these interactions lead to pathophysiological events such as the ones observed in medulloblastoma or glioblastoma brain tumorigenesis? Notch and Hedgehog define fundamental cell signaling mechanisms controlling metazoan development. They have emerged as contributing factors in glioblastoma and medulloblastoma, ones of the most common and aggressive forms of brain tumors. Given the complexity and context-dependence of both Notch and Hedgehog signal modulations, a systematic molecular characterization of Notch- and Hedgehog-related proteins in brain cells should shed light on the complex molecular mechanisms that govern these pathways during brain tumorigenesis. The Rual lab is generating a comprehensive map of the Notch and Hedgehog molecular networks in brain cells. This “interactome” approach has allowed us to uncover several proteins as potential novel modulators of Notch or Hedgehog signals in brain cells, e.g. L3MBTL3 and PIN1, respectively. Upon validation of these candidates in cell-based and in vivo models of brain tumorigenesis, our project should offer the means to manipulating the Notch and Hedgehog molecular networks for therapeutic benefit. Our projects on the Notch and Hedgehog pathways are sponsored by the St. Baldrick's Foundation and the University of Michigan M-Cubed program. Previous funding supports for these projects also include the Michigan Institute for Clinical & Health Research (MICHR), the CONquer canCER Now Foundation (CONCERN), the Childhood Brain Tumor Foundation (CBTF), the Rogel Cancer Center and the Association for Research of Childhood Cancer (AROCC).