# Targeting CK2 oncogenic pathway to overcome drug resistance in high-risk leukemia

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $353,876

## Abstract

SUMMARY
The Ikaros (IKZF1) gene encodes a DNA-binding protein that functions as a tumor suppressor and a
transcriptional regulator in leukemia. Deletion of one Ikaros allele results in the development of high-risk B-cell
acute lymphoblastic leukemia (B-ALL) that is resistant to chemotherapy and has a poor prognosis. Our recently
published data show that CK2 (Casein Kinase II), an oncogenic kinase that is overexpressed in B-ALL,
phosphorylates Ikaros, which reduces Ikaros DNA-binding affinity and abolishes its activity as a transcriptional
regulator. Based on these findings we designed a novel B-ALL treatment strategy to restore Ikaros function by
targeting CK2. The inhibition of CK2 with a specific inhibitor, CX-4945, as a single drug, restored Ikaros ability
to regulate transcription in high-risk B-ALL with deletion of one Ikaros allele and showed therapeutic efficacy in
a preclinical model of this disease. Our new preliminary data suggest that CK2 impairs the ability of Ikaros to
repress transcription of genes essential to the folic acid metabolism pathway: MTHFD1 (methylene-
tetrahydrofolate dehydrogenase NADP+ dependent 1), MTR (5-methyltetrahydrofolate-homocysteine methyl-
transferase) and TYMS (Thymidylate Synthase), as well as the anti-apoptotic gene, BCL-XL. In leukemia, high
expression of the folic acid pathway genes and BCL-XL are associated with increased resistance to
methotrexate and doxorubicin treatment, respectively. Treatment with the CK2-specific inhibitor, CX-4945,
restored Ikaros-mediated repression of the MTHFD1, MTR, TYMS and BCL-XL genes in primary high-risk B-
ALL cells. In vitro treatment of high-risk B-ALL with CX-4945 in combination with methotrexate, or doxorubicin
exhibits a strong synergistic cytotoxicity. We hypothesize that overexpression of CK2 in high-risk B-ALL
impairs Ikaros ability to transcriptionally repress the folic acid pathway and Bcl-XL genes and that CK2
inhibition will restore Ikaros tumor suppressor activity as a transcriptional repressor of these genes in
high-risk B-ALL cells resulting in increased sensitivity to methotrexate and doxorubicin treatment. We
will test this hypothesis in vivo, using patient-derived xenografts (PDX) from pediatric patients with high-risk B-
ALL in the following specific aims: In Aim 1, we will establish the therapeutic efficacy of combination
treatment with the CK2 inhibitor (CX-4945) and the folic acid pathway inhibitor (methotrexate) in a
preclinical model of high-risk B-ALL and determine the molecular mechanisms that restore Ikaros ability to
repress folic acid pathway genes. In Aim 2, we will evaluate the in vivo efficacy of combination therapy
with CX-4945 and doxorubicin and analyze the mechanism that restores Ikaros–mediated repression of
BCL-XL in high-risk B-ALL. In Aim 3, we will identify the mechanisms through which high expression of
CK2 regulates drug resistance and Ikaros tumor suppressor function in B-ALL. Results of the proposed
project would establish t...

## Key facts

- **NIH application ID:** 9934158
- **Project number:** 5R01CA213912-04
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Sinisa Dovat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,876
- **Award type:** 5
- **Project period:** 2017-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934158

## Citation

> US National Institutes of Health, RePORTER application 9934158, Targeting CK2 oncogenic pathway to overcome drug resistance in high-risk leukemia (5R01CA213912-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9934158. Licensed CC0.

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