HomeResearchIntramural ResearchResearch Branches at NHGRIGenetics and Molecular Biology Branch Liu Lab

Paul P. Liu, M.D., Ph.D. Senior Investigator Genetics and Molecular Biology Branch Head Oncogenesis and Development Section M.D. Capital Institute of Medicine, Beijing, China, 1982 Ph.D. University of Texas, 1991 (301) 402-2529 (301) 402-4929 pliu@nhgri.nih.gov Building 49, Room 3A26 49 Convent Dr, MSC 4442 Bethesda, MD 20892-4442 Selected Publications Postdoctoral Position: Transcriptional Network Involved in Leukemia Development

Dr. Liu's laboratory investigates the genetic control of hematopoiesis, the process through which pluripotent hematopoietic stem cells differentiate into all of the types of mature cells that circulate in the bloodstream. His group has a particular interest in leukemia, which strikes an estimated 26,000 Americans each year. Leukemia is an example of hematopoiesis gone awry, and when it develops, the body produces large numbers of abnormal blood cells, or blasts. In acute leukemia, the blasts are too immature to carry out their normal functions, and symptoms of dysfunction appear rapidly.

Leukemias frequently are associated with abnormalities of chromosomes, such as translocations, inversions, and deletions. In one form of human acute myeloid leukemia (AML), the genetic defect is an inversion on chromosome 16. Dr. Liu’s laboratory found that this inversion generates a fusion gene between the core binding factor β gene (CBFβ) and MYH11, the gene encoding smooth muscle myosin heavy chain. His group also demonstrated that the CBFβ-MYH11 fusion gene, through its encoded fusion protein, CBFβ-SMMHC, blocks normal hematopoiesis in transgenic mice and makes them susceptible to leukemia. They further demonstrated in transgenic mice that the expression of the CBFβ-MYH11 fusion gene is necessary but not sufficient for leukemia to develop; they have identified a number of other genes that may act in concert with the fusion gene to cause AML. Dr. Liu’s laboratory is looking for downstream target genes of the CBFβ-SMMHC fusion protein and are testing new therapeutic approaches for AML in mice that specifically counteract the function of CBFβ-MYH1.

To determine the role of CBFβ in hematopoiesis and other developmental processes, Dr. Liu's group has generated mice with a CBFBGFP “knock-in” fusion. They used the mice to examine the expression pattern of the CBFβ protein in different lineages of adult hematopoietic cells and found that it is expressed uniformly in all cell lineages except B lymphocytes and erythroid cells. CBFβ expression decreases during maturation of B cells in the adult bone marrow; it is not expressed at all in nucleated erythroid precursors. Thus, CBFβ is required for myeloid and lymphoid differentiation, but it does not play a critical role in erythroid differentiation. Recent studies from Dr. Liu's laboratory have provided more direct evidence that CBFβ plays an important role in T lymphocyte differentiation. They also found that CBFB-GFP mice have reduced CBFβ activity, and homozygous mice display bone formation defects similar to those in a human disease called cleidocranial dysplasia. This suggests that CBFβ plays a very important role in bone formation, which is a focus of further study in Dr. Liu's laboratory.

In parallel, Dr. Liu's group is generating zebrafish mutants with defects in blood formation using chemical mutagenesis techniques. Through genetic mapping and positional cloning, they are seeking to identify hematopoietic genes that may be altered in these mutants. They already have identified one zebrafish mutant, called vlad tepes (the historical name for Dracula), that has few or no blood cells at the onset of circulation. Dr. Liu's laboratory identified a novel nonsense mutation in the gata1 gene in this zebrafish model that results in the bloodless phenotype. The mutation causes a truncated protein that is unable to bind DNA or mediate gata-specific transactivation. Because gata1 plays an essential role in zebrafish hematopoiesis, and there is a significant conservation of function between mammals and zebrafish, this zebrafish mutant offers a powerful tool for future studies of the hematopoietic pathway.

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Last Updated: August 22, 2008