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The Liu laboratory investigates the molecular mechanisms underlying hematopoietic stem cell (HSC) self-renewal and pathogenesis of clonal hematopoiesis of indeterminate potential (CHIP), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). The long-term goal of our research is to identify novel regulators of leukemia-initiating cells (LICs), understand the molecular mechanisms by which they control LIC self-renewal and expansion, and develop novel therapeutic strategies to eliminate leukemia-initiating cells and improve leukemia treatment. We utilize molecular, genetic, immunological, biochemical, and pharmacological approaches as well as unbiased genome wide studies, including RNA-seq, ChIP-seq, ATAC-seq, HiC and whole genome sequencing, as well as proteomic approaches to investigate the molecular basis of HSC self-renewal and leukemogenesis.

Project 1: The role of tumor suppressor p53 in CHIP, MDS, and AML

While the roles of tumor suppressor p53 in solid tumors have been well defined, its role in normal and malignant hematopoiesis is not fully understood. We discovered that wild type p53 plays a critical role in regulating hematopoietic stem cell quiescence (Liu et al., Cell Stem Cell, 2009). Acquired somatic mutations in the TP53 gene ranks in the top five among genes mutated in clonal hematopoiesis of indeterminate potential (CHIP). Clinical studies suggest that HSCs with TP53 mutations undergo clonal expansion during aging. However, there is a significant gap in knowledge regarding the mechanisms by which TP53 mutations promote CHIP progression and drive MDS and AML pathogenesis. We discovered that TP53 mutations identified in CHIP and MDS drive clonal hematopoiesis through modulating epigenetic pathway (Chen et al., Leukemia, 2018; Chen et al., Nature Communications, 2019). Leukemia patients who exhibit somatic mutations in the tumor suppressor gene TP53 are associated with advanced disease and poor prognosis. We will investigate the mechanisms by which gain-of-function (GOF) mutant p53 drives MDS and AML and develop novel therapeutic approaches that will be effective for MDS and AML patients with TP53 mutations.

Project 2: Phosphatase PRL2 in HSC self-renewal and leukemogenesis

The PRL (phosphatase of regenerating liver) family of phosphatases, consisting of PRL1, PRL2, and PRL3, represents an intriguing group of proteins being validated as biomarkers and therapeutic targets in human cancers. We discovered that phosphatase PRL2 plays an important role in regulating HSC self-renewal and proliferation. We also found that PRL2 mediates and sustains SCF/KIT signaling in hematopoietic stem and progenitor cells. Thus, PRL2 plays critical roles in regulating HSC self-renewal and mediating SCF/KIT signaling (Kobayashi et al., Stem Cells, 2014; Kobayashi et al., Stem Cells, 2017). We recently found that PRL2 is important for the survival and proliferation of human acute leukemia cells (Kobayashi et al., Leukemia, 2017a; Kobayashi et al., Leukemia, 2017b). We will determine the effect of genetic or pharmacologic inhibition of PRL2 on human AML cells and identify the mechanism by which PRL2 contributes to the pathogenesis of AML. Our studies will likely establish PRL2 as a therapeutic target in human AML and facilitate the development of clinically useful PRL2 inhibitors.

Project 3: Polycomb Repressive Complex 1 (PRC1) in HSC self-renewal and terminal differentiation

Polycomb group (PcG) proteins are epigenetic gene silencers that have been implicated in stem cell maintenance and cancer development. My lab demonstrated that the Polycomb group (PcG) protein Bmi1, which plays key roles in stem cell self-renewal and oncogenesis, is a critical downstream target of the PI3K/Akt pathway. We discovered that Akt phosphorylates Bmi1 at serine 316 in vivo and Akt-mediated phosphorylation of Bmi1 inhibits its functions in hematopoietic cells (Liu et al., Science Signaling, 2012). While Bmi1 is important for stem cell maintenance, its role in lineage commitment is largely unknown. We identified Bmi1 as a novel regulator of erythroid development. We discovered that loss of Bmi1 in erythroid progenitor cells results in decreased transcription of multiple ribosomal protein genes and impaired ribosome biogenesis. Thus, Bmi1 promotes erythroid development through regulating ribosome biogenesis (Gao et al., Stem Cells, 2015). In addition, we found that Bmi1 is important for B-1a cell self-renewal (Kobayashi et al., Journal of Immunology, 2020). Further, we found that Bmi1 represses Wnt signaling in hematopoietic stem and progenitor cells (Yu et al., Stem Cell Reviews and Reports, 2021). Genetic and biochemical studies indicate that Polycomb group proteins exist in at least two protein complexes, Polycomb repressive complex 2 (PRC2) and Polycomb repressive complex 1 (PRC1), that act in concert to initiate and maintain stable gene repression. We will investigate the role of PRC1 complex in regulating HSC behavior and decipher how PRC1 mediates gene silencing in hematopoietic stem cells.

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