Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth

Pizzi, Marco; Agostinelli, Claudio; Fuligni, Fabio; Benvenuti, Pietro; Mandato, Elisa; Casellato, Alessandro; Semenzato, Gianpietro; Pileri, Stefano

doi:10.18632/oncotarget.3446

Cited by 33 publications

(39 citation statements)

References 36 publications

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“…Several investigators reported that CK2 is overexpressed and activated in a variety of hematological malignancies such as multiple myeloma (40, 41), mantle cell lymphoma (40, 41), follicular lymphoma (42), diffuse large B-cell lymphoma (42), acute B-lymphoblastic leukemia (43–45), and CLL (46–49). These observations led to the development of CK2 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex

Rozovski

Harris

et al. 2017

Molecular Cancer Research

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In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that co-immunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T-cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that CD5 and BLNK co-expressed in CLL, but not in normal B- or T-cells, are required for STAT3 phosphorylation. To elucidate the relationship of CD5 and BLNK to CK2 and STAT3, STAT3 was immunoprecipitated from CLL cells and CK2, CD5, and BLNK were detected in the immunoprecipitate. Conversely, STAT3, CD5, and BLNK were in the immunoprecipitate of CLL cells immunoprecipitated with CK2 antibodies. Furthermore, siRNA knockdown of CD5 or BLNK, or treatment with CD5-neutralizing antibodies significantly reduced the levels of serine pSTAT3 in CLL cells. Finally, confocal microscopy determined that CD5 is cell membrane bound and fractionation studies revealed that the CK2/CD5/BLNK/STAT3 complex remains in the cytoplasm, whereas serine pSTAT3 is shuttled to the nucleus. Implications These data show that the cellular proteins CK2, CD5, and BLNK are required for constitutive phosphorylation of STAT3 in CLL. Whether this protein complex phosphorylates other proteins or inhibiting its activity would have clinical benefit in patients has yet to be determined.

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Section: Discussionmentioning

confidence: 99%

Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex

Rozovski

Harris

et al. 2017

Molecular Cancer Research

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“…CK2 is upregulated as an oncogene in many human cancers including kidney (27), breast (28), and other cancers (29, 30). CK2 inhibitors have been actively tested in multiple cancer types in preclinical and clinical trials (30).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function

et al. 2016

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Loss of von Hippel Lindau (VHL) protein function is a key driver of VHL diseases, including sporadic and inherited clear cell renal cell carcinoma. Modulation of the proteostasis of VHL, especially missense point-mutated VHL, is a promising approach to augmenting VHL levels and function. VHL proteostasis is regulated by multiple mechanisms including folding, chaperone binding, complex formation, and phosphorylation. Nevertheless, many details underlying the regulations of VHL proteostasis are unknown. VHL is expressed as two variants, VHL30 and VHL19. Furthermore, the long form variant of VHL was often detected as multiple bands by Western blotting. However, how these multiple species of VHL are generated and whether the process regulates VHL proteostasis and function are unknown. We hypothesized that the two major species are generated by VHL protein cleavage, and the cleavage regulates VHL proteostasis and subsequent function. We characterized VHL species using genetic and pharmacologic approaches and showed that VHL was first cleaved at the N-terminus by chymotrypsin C before being directed for proteasomal degradation. Casein kinase 2-mediated phosphorylation at VHL N-terminus was required for the cleavage. Furthermore, inhibition of cleavage stabilized VHL protein, thereby promoting HIF downregulation. Our study reveals a novel mechanism regulating VHL proteostasis and function, which is significant for identifying new drug targets and developing new therapeutic approaches targeting VHL deficiency in VHL diseases.

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“…Pioneering work in mouse models demonstrated that CK2 overexpression may synergize with alterations of FasL, TP53, and c‐Myc in sustaining lymphocyte growth or malignant phenotype . Subsequent work has shown that CK2 is overexpressed in human aggressive lymphomas: a panel of 103 GC‐derived NHL was analyzed by immunohistochemistry for the expression of CK2α and CK2β . The two subunits were found on average markedly expressed across all the NHL subtypes, with Burkitt lymphomas displaying the highest protein levels.…”

Section: Ck1 and Ck2 In Lymphoid Malignanciesmentioning

confidence: 98%

New responsibilities for aged kinases in B‐lymphomas

Manni

Arjomand

Visentin

et al. 2019

Hematological Oncology

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The knowledge accumulated over the last decade on B-cell-derived non-Hodgkin lymphoma (B-NHL) pathogenesis has led to the identification of several molecular abnormalities, opening new perspectives in the design of novel therapies. Indeed, drugs targeting specific biochemical pathways critical for B-NHL cell survival, proliferation, and fitness within the malignant microenvironment are now available to the clinician: the B-cell receptor signaling inhibitors of BTK, PI3Kδ, ζ, γ, and SYK or the pro-apoptotic BH3-mimetics are clear examples of it. Moreover, it is emerging that malignant B-cell growth is sustained not only by mutations in oncogenes/tumor suppressors but also by the "addiction" to nononcogene (ie, nonstructurally altered) molecules. In this regard, a consistent body of data has established that the Ser/Thr kinases CK1, CK2, and GSK3 are involved in malignant lymphocyte biology and act as pro-survival and signaling-boosting molecules, both in precursor and mature B-cell tumors. Currently, an experimental and clinical groundwork is available, upon which to design CK1-, CK2-, and GSK3-directed antilymphoma/leukemia therapies. In this review, we have examined the main features of CK1, CK2, and GSK3 kinases, summarized the data in B-NHL supporting them as suitable therapeutic targets, and proposed a perspective on potential future research development. K E Y W O R D S B lymphocytes, CK1, CK2, GSK3, lymphoma, protein kinase 1 | EVOLVING PARADIGMS IN NON-HODGKIN LYMPHOMAS Non-Hodgkin lymphomas (NHL) are collectively the most frequent hematologic cancer, among the top 10 most frequent malignant tumors worldwide. 1 B-cell-derived NHL (B-NHL) are by far more frequent than T-cell-derived NHL, and between them, tumors arising from the mature B cell are more frequent. The 2016 World Health Organization (WHO) classification of NHL has recognized approximately 60 distinct entities. 2 In the group of B-NHL, diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype, accounting for 35% of all B-NHL, followed by follicular lymphoma (FL), which accounts for up to 20% to 25% of B-NHL. These two B-NHL subtypes originate from germinal center (GC) centrocytes/centroblasts. 3 However, a proportion of DLBCL are from post-GC origin, the so called "activated B-cell" (ABC)-type DLBCL. Patients affected by this latter subtype are believed to be subjected to a more dismal prognosis as compared with those with GC B-cell (GCB) type. 4 Other less frequent B-NHL are mantle cell lymphoma (MCL, approximately 10% of all B-NHL), marginal zone lymphoma (MZL, about 5% of all B-NHL), small lymphocyte lymphoma/chronic lymphocytic leukemia (SLL/CLL, 5%), lymphoplasmacytic lymphoma (LPL, 3%). 2 Deep sequencing of the genome and the transcriptome has provided a great amount of data describing mutations and aberrant expression of cell signaling molecules. For instance, the molecular classification of DLBCL has been progressively refined from the seminal paper of Alizadeh describing the GCB/ABC/undetermined subtypes, 4 based on gene expres...

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Protein kinase CK2 is widely expressed in follicular, Burkitt and diffuse large B-cell lymphomas and propels malignant B-cell growth

Cited by 33 publications

References 36 publications

Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex

Constitutive Phosphorylation of STAT3 by the CK2–BLNK–CD5 Complex

Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function

New responsibilities for aged kinases in B‐lymphomas

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