Abstract
BackgroundThe 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.MethodsHere, 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.ResultsCX-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.ConclusionsWe 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.
Highlights
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-Acute lymphoblastic leukemia (ALL))
In B cell acute lymphoblastic leukemia (B-ALL) distinct molecular aberrations contribute to leukemogenesis including mutations, chromosomal translocations or epigenetic dysregulation [1, 2]
CX-4945 affects Casein Kinase II (CK2) activity, PI3K/AKT signaling and cell biology parameters SEM and RS4;11 cells were incubated with 5 μM CX-4945 for up to 24 h
Summary
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). 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. Increased phosphorylation of PTEN reduces its phosphatase activity resulting in anti-apoptotic downstream signaling [6]. Apart from increased phosphorylation hypermethyl ation-induced decreased PTEN transcription has been reported in several tumors including B-ALL [7]. Hypomethylating agents (HMA) can restore the PTEN activity and inhibit PI3K/AKT downstream signaling [8]. We demonstrated that HMA induce apoptosis and cell cycle arrest and inhibit proliferation in human B-ALL [10]
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