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Open Sadiesteffens Dissertation Final.Pdf The Pennsylvania State University The Graduate School College of Medicine MECHANISM OF DRUG ACTION OF THE SPECIFIC CK2 INHIBITOR CX-4945 IN ACUTE MYELOID LEUKEMIA A Dissertation in Biomedical Sciences by Sadie Lynne Steffens 2015 Sadie Lynne Steffens Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2015 The dissertation of Sadie Lynne Steffens was reviewed and approved* by the following: Sinisa Dovat Physician, Associate Professor of Pediatrics, Pharmacology, & Biochemistry Director, Translational Research – Four Diamonds Pediatric Cancer Research Center Dissertation Advisor Chair of Committee Barbara A. Miller Physician, Professor of Pediatrics Chief, Division of Pediatric Hematology/Oncology Sergei A. Grigoryev Professor of Biochemistry and Molecular Biology Jong K. Yun Associate Professor of Pharmacology Ralph L. Keil Associate Professor of Biochemistry and Molecular Biology Chair, Biomedical Sciences Graduate Program *Signatures are on file in the Graduate School ii ABSTRACT Acute myeloid leukemia (AML) is a malignant disease of the myeloid line of blood cells and is characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. Cytarabine and other currently available treatments for acute myeloid leukemia are highly toxic and insufficient, as more than half of all AML patients develop resistance to chemotherapeutic agents. Since AML often affects older people who are less tolerant of chemotherapy, there is need for novel, targeted, less toxic drugs in order to improve survival for this disease. Casein Kinase II (CK2) is a pro-oncogenic serine/threonine kinase that is essential for cellular proliferation. Overexpression or increased CK2 activity is associated with various types of human malignancies. In hematopoietic cells, increased CK2 expression is associated with malignant transformation and development of leukemia. Increased CK2 activity is associated with a poor prognosis in AML. Targeted inhibition of CK2 with a novel, specific inhibitor produced a strong anti-leukemia effect in vitro and in pre- clinical models. However, the mechanism through which CK2 inhibitors exert an anti- leukemia effect is unknown. The goal of our project is to identify the mechanism of the therapeutic activity of CK2 inhibition using CX-4945 in AML. Ikaros is a zinc finger, DNA-binding protein that is encoded by the IKZF1 gene and acts as a tumor suppressor in hematopoietic malignancies. Deletion or functional inactivation of Ikaros is associated with development of high-risk acute lymphoblastic leukemia (ALL) as well as AML. Previously published data showed that CK2 directly iii phosphorylates Ikaros at multiple evolutionarily-conserved sites. The CK2-mediated phosphorylation of Ikaros results in reduced DNA-binding affinity and loss of Ikaros function as a transcriptional regulator of gene expression. Inhibition of CK2 restores Ikaros function as a tumor suppressor and produces an anti-leukemia effect in ALL. Based on these data, we hypothesized that one of the mechanisms of therapeutic action of CK2 inhibitors in AML involves restoration of Ikaros function as a transcriptional regulator of genes involved in malignant transformation. Genome-wide binding studies using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-Seq) demonstrated that inhibition of CK2 via CX- 4945 in U937 and primary AML cells enhances Ikaros binding affinity at the promoter regions of its target genes. We used gain-of-function and loss-of-function experiments to determine how Ikaros regulates several novel target genes involved in malignant transformation and drug resistance. Results demonstrated that Ikaros directly represses transcription of the BCL2A1 gene, which promotes leukemogenesis and has an anti- apoptotic function. We show that the ability of Ikaros to repress transcription of BCL2A1 is impaired in AML, overexpression of BCL2A1 is a negative prognostic marker, and anti-apoptotic mechanisms contribute to resistance to chemotherapy. Repression of BCL2A1 results in increased apoptosis. The ability of Ikaros to repress BCL2A1 transcription is impaired by CK2. Inhibition of CK2 via CX-4945 increases Ikaros binding at the BCL2A1 promoter, resulting in transcriptional repression of BCL2A1. Increased Ikaros binding to the BCL2A1 promoter is associated with formation of repressive chromatin that is characterized by the loss of the positive marker H3K4me2 iv and increase in the negative marks H3K9me3 and H3K27me3. Since BCL2A1 has an anti-apoptotic function, we tested whether CK2 inhibition increases susceptibility of AML cells to apoptosis. Results showed that CK2 inhibition increases apoptosis of AML cells and that the CK2 inhibitor CX-4945 has synergistic therapeutic effects in combination with a standard drug for AML, Doxorubicin. These data indicate a new Ikaros target gene, one mechanism for the therapeutic activity of CK2 inhibition, and a novel combination treatment for AML. Similar functional experiments were performed on four additional Ikaros target genes that were identified by ChIP-Seq (MTHFR, CDA, DLX1, and DLX2). Results demonstrated that CK2 impairs transcriptional regulation of these genes by Ikaros in AML. Treatment with CK2 inhibitor restores Ikaros-mediated regulation of these genes. Since two of the newly-identified Ikaros target genes are known to be involved in drug resistance, the therapeutic effect of the CK2 inhibitor CX-4945 has been tested in combination with additional chemotherapeutic agents, and results showed a synergistic effect of these combination treatments in AML cells. Finally, a systems biology approach was used to determine the effect of CK2 inhibition on the epigenome and transcriptome of AML cells. The analysis revealed that CK2 inhibition results in alterations in the epigenomic signature of AML cells. The prominent changes involved alteration of enhancer and super-enhancer landscapes, which were associated with transcriptional regulation of many genes that are critical for cellular proliferation. v In summary, our results demonstrate that the therapeutic effect of CK2 inhibition in AML cells involves restoration of Ikaros function as a tumor suppressor and transcriptional regulator. Our results have identified novel pathways that are regulated by Ikaros as well as an epigenomic landscape that is regulated by CK2. These data led to the development of novel combination treatments for AML which showed synergy when tested on AML cells. Our results provide a mechanistic rationale for development of novel, targeted treatments for AML. vi TABLE OF CONTENTS List of Figures .............................................................................................................. xi List of Tables ............................................................................................................... xiv List of Abbreviations ................................................................................................... xv Chapter 1 Introduction and Literature Review ............................................................ 1 Introduction ........................................................................................................... 2 Current Treatments for AML ................................................................................ 8 Casein Kinase 2 as a Drug Target in AML ........................................................... 9 The CK2 Inhibitor CX-4945 as a Potential Treatment for AML ......................... 11 Ikaros as a Tumor Suppressor in Leukemia ......................................................... 12 Ikaros in Development .......................................................................................... 15 Regulation of Ikaros by CK2 ................................................................................ 17 The Role of Epigenetics in Differentiation ........................................................... 20 Dissertation Goals and Hypotheses ...................................................................... 21 Models .................................................................................................................. 23 Ikaros Target Genes Identified by ChIP-Seq ........................................................ 24 Tables .................................................................................................................... 27 Figures .................................................................................................................. 41 References ............................................................................................................. 47 Chapter 2 Therapeutic Efficacy of the Specific CK2 Inhibitor CX-4945 in AML Involves Transcriptional Repression of BCL2A1 by Ikaros ................................. 57 Abstract ................................................................................................................. 58 Introduction ........................................................................................................... 59 Experimental Procedures ...................................................................................... 61 Cells, Cell Culture, and Reagents .................................................................. 61 ChIP-Seq experiments ................................................................................... 61 Antibodies .....................................................................................................
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