Combined Casein Kinase II inhibition and epigenetic modulation in acute B-lymphoblastic leukemia

Abstract

Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (10.1186/s12885-019-5411-0) contains supplementary material, which is available to authorized users.

Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy – potential clinical relevance

“…Combined treatment with the CK2 inhibitor and the DNAhypomethylating agent significantly decreased the metabolic activity of SEM and NALM-6 cells (two B-ALL cell lines), without affecting their proliferation rate. More interestingly, it was found that co-administration of decitabine and CX-4945 markedly reduced the proliferation and dissemination of SEM cells in a mouse xenograft model [42].…”

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

“…One of the emerging players in T-ALL biology is CK2 (also known as casein kinase 2), a constitutively active serine/threonine protein kinase whose activity accounts for nearly 20% of the human phosphoproteome and is implicated in a myriad of cellular processes [7,8]. The role of CK2 in the maintenance of malignant phenotypes has been extensively studied in solid tumors (reviewed in [9]), and in hematological malignancies (reviewed in [10] and [11]), including in ALL [2,[12][13][14][15][16][17][18]. The role of CK2 in T-ALL in particular, with evidence that CK2 accelerates T-cell leukemogenesis in mice, has been recognized for years [19].…”

Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia

“…( a,b ) Protein expression of phosphorylated and total AKT was measured by immunofluorescence staining ( a ) and immunoblotting ( b ). Cells of patients #0122 and #0159 were orthotopically xenografted into NSG mice as described in [ 33 , 34 ] and spleen cells were subsequently harvested for further analysis. ( a ) Expression of pAKT was determined by immunofluorescence using the LSM780 confocal microscope (Zeiss) at 20-fold magnification (left panel).…”