Paul P. Liu, M.D., Ph.D.
Genetics and Molecular Biology Branch
Building 49, Room 3A26
49 Convent Drive
Bethesda, MD 20892
Dr. Liu's laboratory investigates the molecular mechanism of leukemia, a disease that strikes approximately 43,000 Americans each year. His group has a particular interest in 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.
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, these blasts are too immature to carry out their normal functions, and symptoms of dysfunction appear quickly. Leukemias are frequently associated with chromosome abnormalities and defects such as translocations, inversions, and deletions. One form of human acute myeloid leukemia (AML) is associated with an inversion of chromosome 16. Dr. Liu's laboratory found that this inversion generates a fusion gene between the core binding factor β gene (CBFB) and MYH11, the gene encoding smooth muscle myosin heavy chain.
To study the CBFB-MYH11 fusion gene, Dr. Liu's group generated transgenic mouse models. With these models, they demonstrated that the fusion gene blocks normal hematopoiesis through its encoded fusion protein (CBFβ-SMMHC), leading to AML susceptibility. Dr. Liu's group has determined the importance of functional domains in the mouse Cbfb-MYH11 fusion gene by generating and analyzing mice expressing truncated CBFβ-SMMHC. They made the novel observation that Cbfb-MYH11 induces AML without dominant repression of another gene called RUNX1, which was previously believed to be the key function of this fusion gene.
More recently, Dr. Liu's laboratory has identified novel CBFB-MYH11 target genes during leukemia development using mouse models. With the identified target genes, his group was able to identify and enrich for leukemia stem cells, which are responsible for initiating leukemia and for relapse after treatments. Characterization of such leukemia stem cells may help to develop approaches to leukemia cell eradication in patients. In fact, through a collaboration with the NIH Chemical Genomics Center, Dr. Liu's group conducted a chemical library screen and is in the process of developing and testing novel anti-leukemia compounds in transgenic mouse AML models.
In parallel, Dr. Liu's group is studying genetic control of hematopoiesis in the zebrafish, which is an excellent vertebrate model for embryonic development and for conducting systematic genetic screens. Using chemical mutagenesis techniques, zebrafish mutants are generated that carry defects in hematopoiesis. Through genetic mapping and positional cloning, Dr. Liu's laboratory seeks to identify the genes that are altered in these mutants. One zebrafish mutant, vlad tepes, has few or no blood cells at the onset of circulation. Dr. Liu's group identified a novel nonsense mutation in the gata1 gene as the cause for the bloodless phenotype in the vlad tepes fish. In mammals, the transcription factor GATA1 is required for normal erythroid development. This first gata1 mutation identified in the zebrafish demonstrates significant functional conservation between mammalian and zebrafish hematopoiesis, and offers a powerful tool for future studies of hematopoiesis in zebrafish.
Dr. Liu's laboratory has more recently used high-throughput reverse genetic screening systems to efficiently generate fish lines carrying mutations in any genes of interest, which can then be used for further phenotypic and genetic studies. Using this approach, the group generated a fish line with a mutation in the ,em>runx1 gene, which is frequently mutated in human leukemias. This novel zebrafish mutant enabled Dr. Liu's group to more accurately determine the gene's function in hematopoiesis. In addition, the runx1 mutant fish as well as other transgenic fish lines have been used successfully in the screening of novel compounds that target the leukemia-related runx1 and cbfb genes. This technology will therefore be highly useful for generating fish models of human disease and complex traits, as well as for the development of novel treatments.
Cheng L, Hansen NF, Zhao L, Du Y, Zou C, Donovan FX, Chou BK, Zhou G, Li S, Dowey SN, Ye Z, NISC Comparative Sequencing Program, Chandrasekharappa SC, Yang H, Mullikin JC, Liu PP. Low incidence of DNA sequence variation in human induced pluripotent stem cells generated by nonintegrating plasmid expression. Cell Stem Cell. 2012;10(3):337-44.
Bresciani E, Carrington B, Wincovitch S, Jones M, Gore AV, Weinstein BM, Sood R, Liu PP. CBFβ and RUNX1 are required at 2 different steps during the development of hematopoietic stem cells in zebrafish. Blood. 2014;124(1):70-8.
Kamikubo Y, Zhao L, Wunderlich M, Corpora T, Hyde RK, Paul TA, Kundu M, Garrett L, Compton S, Huang G, Wolff L, Ito Y, Bushweller J, Mulloy JC, Liu PP. Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1. Cancer Cell. 2010;17(5):455-68.
Connelly JP, Kwon EM, Gao Y, Trivedi NS, Elkahloun AG, Horwitz MS, Cheng L, Liu PP. Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects. Blood. 2014;124(12):1926-30.
Cunningham L, Finckbeiner S, Hyde RK, Southall N, Marugan J, Yedavalli VR, Dehdashti SJ, Reinhold WC, Alemu L, Zhao L, Yeh JR, Sood R, Pommier Y, Austin CP, Jeang KT, Zheng W, Liu P. Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBFβ interaction. Proc Natl Acad Sci U S A. 2012;109(36):14592-7.