Department of Medicine, Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057, Rostock, Germany.
Institute for Biostatistics and Informatics in Medicine and Ageing, Rostock University Medical Center, Ernst-Heydemann-Straße 8, 18057, Rostock, Germany.
BMC Cancer. 2019 Mar 6;19(1):202. doi: 10.1186/s12885-019-5411-0.
The tumor suppressor protein phosphatase and tensin homolog (PTEN) is a key regulator of the PI3K/AKT pathway which is frequently altered in a variety of tumors including a subset of acute B-lymphoblastic leukemias (B-ALL). While PTEN mutations and deletions are rare in B-ALL, promoter hypermethylation and posttranslational modifications are the main pathways of PTEN inactivation. Casein Kinase II (CK2) is often upregulated in B-ALL and phosphorylates both PTEN and DNA methyltransferase 3A, resulting in increased PI3K/AKT signaling and offering a potential mechanism for further regulation of tumor-related pathways.
Here, we evaluated the effects of CK2 inhibitor CX-4945 alone and in combination with hypomethylating agent decitabine on B-ALL proliferation and PI3K/AKT pathway activation. We further investigated if CX-4945 intensified decitabine-induced hypomethylation and identified aberrantly methylated biological processes after CK2 inhibition. In vivo tumor cell proliferation in cell line and patient derived xenografts was assessed by longitudinal full body bioluminescence imaging and peripheral blood flow cytometry of NSG mice.
CX-4945 incubation resulted in CK2 inhibition and PI3K pathway downregulation thereby inducing apoptosis and anti-proliferative effects. CX-4945 further affected methylation patterns of tumor-related transcription factors and regulators of cellular metabolism. No overlap with decitabine-affected genes or processes was detected. Decitabine alone revealed only modest anti-proliferative effects on B-ALL cell lines, however, if combined with CX-4945 a synergistic inhibition was observed. In vivo assessment of CX-4945 in B-ALL cell line xenografts resulted in delayed proliferation of B-ALL cells. Combination with DEC further decelerated B-ALL expansion significantly and decreased infiltration in bone marrow and spleen. Effects in patient-derived xenografts all harboring a t(4;11) translocation were heterogeneous.
We herein demonstrate the anti-leukemic potential of CX-4945 in synergy with decitabine in vitro as well as in vivo identifying CK2 as a potentially targetable kinase in B-ALL.
肿瘤抑制蛋白磷酸酶和张力蛋白同源物（PTEN）是 PI3K/AKT 通路的关键调节因子，该通路在多种肿瘤中经常发生改变，包括一部分急性 B 淋巴细胞白血病（B-ALL）。虽然 PTEN 突变和缺失在 B-ALL 中很少见，但启动子甲基化和翻译后修饰是 PTEN 失活的主要途径。酪蛋白激酶 2（CK2）在 B-ALL 中经常上调，并磷酸化 PTEN 和 DNA 甲基转移酶 3A，导致 PI3K/AKT 信号转导增加，并为进一步调节肿瘤相关途径提供了潜在机制。
在这里，我们评估了 CK2 抑制剂 CX-4945 单独使用和与低甲基化剂地西他滨联合使用对 B-ALL 增殖和 PI3K/AKT 通路激活的影响。我们进一步研究了 CK2 抑制是否增强了地西他滨诱导的低甲基化，并鉴定了 CK2 抑制后异常甲基化的生物学过程。通过纵向全身生物发光成像和 NSG 小鼠外周血流式细胞术评估细胞系和患者来源异种移植中的肿瘤细胞增殖。
CX-4945 孵育导致 CK2 抑制和 PI3K 通路下调，从而诱导细胞凋亡和抗增殖作用。CX-4945 进一步影响肿瘤相关转录因子和细胞代谢调节剂的甲基化模式。未检测到与地西他滨作用基因或过程的重叠。地西他滨单独对 B-ALL 细胞系仅显示出适度的抗增殖作用，但与 CX-4945 联合使用时观察到协同抑制作用。在 B-ALL 细胞系异种移植中的体内评估导致 B-ALL 细胞增殖延迟。与 DEC 联合使用进一步显著减缓 B-ALL 扩张并减少骨髓和脾脏浸润。所有携带 t(4;11)易位的患者来源异种移植的效果均具有异质性。
我们在此证明了 CX-4945 与地西他滨联合在体外以及体内的抗白血病潜力，确定 CK2 是 B-ALL 中潜在的可靶向激酶。
