The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.

• Keywords
• AML, CK1α, CK1ε, CLL, MM, WNT pathway, casein kinase 1, inhibitors, leukemia, umbralisib,
• MeSH
• Molecular Targeted Therapy * MeSH
• Hematologic Neoplasms drug therapy   enzymology   pathology   MeSH
• Casein Kinase I antagonists & inhibitors   chemistry   metabolism   MeSH
• Humans MeSH
• Neoplastic Stem Cells drug effects   metabolism   pathology   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Wnt Signaling Pathway MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Casein Kinase I MeSH
• Antineoplastic Agents MeSH

Classical Hodgkin lymphoma (cHL) has a typical clinical manifestation, with dissemination involving functionally neighboring lymph nodes. The factors involved in the spread of lymphoma cells are poorly understood. Here we show that cHL cell lines migrate with higher rates compared with non-Hodgkin lymphoma cell lines. cHL cell migration, invasion and adhesion depend on autocrine WNT signaling as revealed by the inhibition of WNT secretion with the porcupine inhibitors Wnt-C59/IWP-2, but did not affect cell proliferation. While application of recombinant WNT5A or WNT5A overexpression stimulates HL cell migration, neither WNT10A, WNT10B nor WNT16 did so. Time-lapse studies revealed an amoeboid type of cell migration modulated by WNT5A. Reduced migration distances and velocity of cHL cells, as well as altered movement patterns, were observed using porcupine inhibitor or WNT5A antagonist. Knockdown of Frizzled5 and Dishevelled3 disrupted the WNT5A-mediated RHOA activation and cell migration. Overexpression of DVL3-K435M or inhibition of ROCK (Rho-associated protein kinase) by Y-27632/H1152P disrupted cHL cell migration. In addition to these mechanistic insights into the role of WNT5A in vitro, global gene expression data revealed an increased WNT5A expression in primary HL cells in comparison with normal B-cell subsets and other lymphomas. Furthermore, the activity of both porcupine and WNT5A in cHL cells had an impact on lymphoma development in the chick chorionallantoic membrane assay. Massive bleeding of these lymphomas was significantly reduced after inhibition of WNT secretion by Wnt-C59. Therefore, a model is proposed where WNT signaling has an important role in regulating tumor-promoting processes.

• MeSH
• Models, Biological MeSH
• Biopsy MeSH
• Cell Adhesion genetics   MeSH
• Porcupines MeSH
• Gene Expression MeSH
• Frizzled Receptors metabolism   MeSH
• Hodgkin Disease diagnostic imaging   genetics   metabolism   pathology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Tomography, X-Ray Computed MeSH
• Cell Movement genetics   MeSH
• Cell Proliferation MeSH
• Dishevelled Proteins metabolism   MeSH
• Wnt-5a Protein genetics   metabolism   MeSH
• rhoA GTP-Binding Protein metabolism   MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DVL3 protein, human MeSH Browser
• Frizzled Receptors MeSH
• FZD5 protein, human MeSH Browser
• Dishevelled Proteins MeSH
• Wnt-5a Protein MeSH
• rhoA GTP-Binding Protein MeSH

Frizzleds (FZDs) are unconventional G protein-coupled receptors that belong to the class Frizzled. They are bound and activated by the Wingless/Int-1 lipoglycoprotein (WNT) family of secreted lipoglycoproteins. To date, mechanisms of signal initiation and FZD-G protein coupling remain poorly understood. Previously, we showed that FZD6 assembles with Gαi1/Gαq (but not with Gαs, Gαo and Ga12/13), and that these inactive-state complexes are dissociated by WNTs and regulated by the phosphoprotein Dishevelled (DVL). Here, we investigated the inactive-state assembly of heterotrimeric G proteins with FZD4, a receptor important in retinal vascular development and frequently mutated in Norrie disease or familial exudative vitreoretinopathy. Live-cell imaging experiments using fluorescence recovery after photobleaching show that human FZD4 assembles-in a DVL-independent manner-with Gα12/13 but not representatives of other heterotrimeric G protein subfamilies, such as Gαi1, Gαo, Gαs, and Gαq The FZD4-G protein complex dissociates upon stimulation with WNT-3A, WNT-5A, WNT-7A, and WNT-10B. In addition, WNT-induced dynamic mass redistribution changes in untransfected and, even more so, in FZD4 green fluorescent protein-transfected cells depend on Gα12/13 Furthermore, expression of FZD4 and Gα12 or Gα13 in human embryonic kidney 293 cells induces WNT-dependent membrane recruitment of p115-RHOGEF (RHO guanine nucleotide exchange factor, molecular weight 115 kDa), a direct target of Gα12/13 signaling, underlining the functionality of an FZD4-Gα12/13-RHO signaling axis. In summary, Gα12/13-mediated WNT/FZD4 signaling through p115-RHOGEF offers an intriguing and previously unappreciated mechanistic link of FZD4 signaling to cytoskeletal rearrangements and RHO signaling with implications for the regulation of angiogenesis during embryonic and tumor development.

• MeSH
• Rho Guanine Nucleotide Exchange Factors metabolism   MeSH
• Fluorescence Recovery After Photobleaching MeSH
• Frizzled Receptors chemistry   metabolism   MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Dishevelled Proteins metabolism   MeSH
• Protein Domains MeSH
• GTP-Binding Protein alpha Subunits, G12-G13 metabolism   MeSH
• Wnt Proteins pharmacology   MeSH
• Fluorescence Resonance Energy Transfer MeSH
• Signal Transduction drug effects   MeSH
• Protein Binding drug effects   MeSH
• Green Fluorescent Proteins metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Rho Guanine Nucleotide Exchange Factors MeSH
• Frizzled Receptors MeSH
• FZD4 protein, human MeSH Browser
• Dishevelled Proteins MeSH
• GTP-Binding Protein alpha Subunits, G12-G13 MeSH
• Wnt Proteins MeSH
• Green Fluorescent Proteins MeSH