Therapeutic value and mechanistic action of PSPC1 in AML

Summary Acute myeloid leukemia (AML) is a biologically and genetically heterogeneous hematopoietic malignancy characterized by the blockage of myeloid cell differentiation and uncontrolled proliferation of immature myeloid cells. Although treatment options for AML have progressed over the past few decades, the 5-year overall survival of AML patients is still <30%. Therefore, there remains a high unmet need to develop novel and more effective AML therapies, which requires a deeper understanding of the pathophysiology of AML and the identification of novel and effective molecular targets. Our preliminary data showed that paraspeckle protein component 1 (PSPC1) is highly overexpressed in virtually all types of human AMLs, and PSPC1 knockdown (KD) profoundly suppresses proliferation, promotes apoptosis, and induces robust differentiation of diverse AML cells and abrogates their leukemogenic capacity. Furthermore, Pspc1 deletion has little effect on hematopoietic stem/progenitor cell (HSPC) function, steady-state hematopoiesis, or normal mouse development. Despite being a member of the Drosophila Behavior/Human Splicing (DBHS) protein family associated with nuclear paraspeckles containing SFPQ and NONO, neither paraspeckles nor NONO is involved in PSPC1-mediated hyperproliferation and myeloid differentiation arrest in AML cells. Moreover, neither the N-terminal RNA recognition/binding motifs nor the C-terminal coiled-coil domain (essential for dimerization) of PSPC1 is important for the pathogenic function of PSPC1 in AML cells. Integrated PSPC1 ChIP-seq and RNA-seq analyses in WT vs. PSPC1 KD AML cells identified key target genes important for oncogenesis, proliferation, survival, and differentiation of AML cells, and motif analysis revealed putative transcription factors (TFs) that may associate with PSPC1 in target gene transcriptional activation and repression. Based on these exciting findings, we hypothesize that PSPC1 acts as a novel determinant for AML leukemogenesis and that PSPC1 inhibition represents a safe and highly effective therapeutic strategy for various AMLs where PSPC1 interacts with key TFs to dictate a unique leukemic transcription program underlying multiple AMLs. To test this hypothesis, we will: 1) use the loss-of-function genetic strategy to further validate that PSPC1 is a novel therapeutic target for AML; 2) determine whether PSPC1 is a common target for AML induced by different AML drivers and whether other oncogenes are required for PSPC1 to induce AML; and 3) dissect the molecular mechanisms by which PSPC1 induces AML by defining PSPC1-regulated common transcriptome and the PSPC1 interactome across multiple AML subentities and studying the contribution of PSPC1 partners/target genes to AML characteristics and leukemogenesis. The success of the proposed studies will gain fundamental knowledge on AML biology and leukemogenesis by establishing PSPC1 as a critical and novel determinant for AML leukemogenesis, which can lead to the breakthrough in AML treatment by developing ways to target PSPC1 using RNAi and/or small molecule inhibitors as a safe and effective therapeutic strategy for various AMLs.