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.

Department of Cytokinetics Institute of Biophysics Academy of Sciences of the Czech Republic 61265 Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University 62500 Brno Czech Republic

TG Therapeutics New York NY 10014 USA

Zobrazit více v PubMed

Lemeer S., Heck A.J. The phosphoproteomics data explosion. Curr. Opin. Chem. Biol. 2009;13:414–420. doi: 10.1016/j.cbpa.2009.06.022. PubMed DOI

Sikes R.A. Chemistry and pharmacology of anticancer drugs. Br. J. Cancer. 2007;97:1713. doi: 10.1038/sj.bjc.6604075. DOI

Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update. Pharmacol. Res. 2020;152:104609. doi: 10.1016/j.phrs.2019.104609. PubMed DOI

Knippschild U., Krüger M., Richter J., Xu P., García-Reyes B., Peifer C., Halekotte J., Bakulev V., Bischof J. The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis. Front. Oncol. 2014;4:96. doi: 10.3389/fonc.2014.00096. PubMed DOI PMC

Cegielska A., Gietzen K.F., Rivers A., Virshup D.M. Autoinhibition of casein kinase I epsilon (CKI epsilon) is relieved by protein phosphatases and limited proteolysis. J. Biol Chem. 1998;273:1357–1364. doi: 10.1074/jbc.273.3.1357. PubMed DOI

Fish K.J., Cegielska A., Getman M.E., Landes G.M., Virshup D.M. Isolation and Characterization of Human Casein Kinase I-Epsilon (Cki), a Novel Member of the Cki Gene Family. J. Biol. Chem. 1995;270:14875–14883. doi: 10.1074/jbc.270.25.14875. PubMed DOI

Petzold G., Fischer E.S., Thomä N.H. Structural basis of lenalidomide-induced CK1α degradation by the CRL4 CRBN ubiquitin ligase. Nature. 2016;532:127–130. doi: 10.1038/nature16979. PubMed DOI

Minzel W., Venkatachalam A., Fink A., Hung E., Brachya G., Burstain I., Shaham M., Rivlin A., Omer I., Zinger A., et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 doi: 10.1016/j.cell.2018.07.045. PubMed DOI PMC

Long A., Zhao H., Huang X. Structural Basis for the Interaction between Casein Kinase 1 Delta and a Potent and Selective Inhibitor. J. Med. Chem. 2012;55:956–960. doi: 10.1021/jm201387s. PubMed DOI

Long A.M., Zhao H., Huang X. Structural basis for the potent and selective inhibition of casein kinase 1 epsilon. J. Med. Chem. 2012;55:10307–10311. doi: 10.1021/jm301336n. PubMed DOI

Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., Shindyalov I.N., Bourne P.E. The Protein Data Bank. Nucleic Acids Res. 2000;28:235–242. doi: 10.1093/nar/28.1.235. PubMed DOI PMC

Schittek B., Sinnberg T. Biological functions of casein kinase 1 isoforms and putative roles in tumorigenesis. Mol. Cancer. 2014;13:231. doi: 10.1186/1476-4598-13-231. PubMed DOI PMC

Xu P., Ianes C., Gärtner F., Liu C., Burster T., Bakulev V., Rachidi N., Knippschild U., Bischof J. Structure, regulation, and (patho-)physiological functions of the stress-induced protein kinase CK1 delta (CSNK1D) Gene. 2019;715:144005. doi: 10.1016/j.gene.2019.144005. PubMed DOI PMC

Jiang S., Zhang M., Sun J., Yang X. Casein kinase 1α: Biological mechanisms and theranostic potential. Cell Commun. Signal. 2018;16:1–24. doi: 10.1186/s12964-018-0236-z. PubMed DOI PMC

Perez D.I., Gil C., Martinez A. Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases. Med. Res. Rev. 2011;31:924–954. doi: 10.1002/med.20207. PubMed DOI

Bernatik O., Ganji R.S., Dijksterhuis J.P., Konik P., Cervenka I., Polonio T., Krejci P., Schulte G., Bryja V. Sequential activation and inactivation of Dishevelled in the Wnt/beta-catenin pathway by casein kinases. J. Biol. Chem. 2011;286:10396–10410. doi: 10.1074/jbc.M110.169870. PubMed DOI PMC

Bryja V., Schulte G., Rawal N., Grahn A., Arenas E. Wnt-5a induces Dishevelled phosphorylation and dopaminergic differentiation via a CK1-dependent mechanism. J. Cell Sci. 2007;120:586–595. doi: 10.1242/jcs.03368. PubMed DOI

Greer Y.E., Rubin J.S. Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. J. Cell Biol. 2011;192:993–1004. doi: 10.1083/jcb.201011111. PubMed DOI PMC

Peters J.M., McKay R.M., McKay J.P., Graff J.M. Casein kinase I transduces Wnt signals. Nature. 1999;401:345–350. doi: 10.1038/43830. PubMed DOI

Vinyoles M., Del Valle-Pérez B., Curto J., Padilla M., Villarroel A., Yang J., de Herreros A.G., Duñach M. Activation of CK1ɛ by PP2A/PR61ɛ is required for the initiation of Wnt signaling. Oncogene. 2017;36:429–438. doi: 10.1038/onc.2016.209. PubMed DOI PMC

Zeng C.M., Chen Z., Fu L. Frizzled Receptors as Potential Therapeutic Targets in Human Cancers. Int J. Mol. Sci. 2018;19:1543. doi: 10.3390/ijms19051543. PubMed DOI PMC

Dijksterhuis J.P., Baljinnyam B., Stanger K., Sercan H.O., Ji Y., Andres O., Rubin J.S., Hannoush R.N., Schulte G. Systematic mapping of WNT-FZD protein interactions reveals functional selectivity by distinct WNT-FZD pairs. J. Biol. Chem. 2015;290:6789–6798. doi: 10.1074/jbc.M114.612648. PubMed DOI PMC

Suraweera N., Robinson J., Volikos E., Guenther T., Talbot I., Tomlinson I., Silver A. Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines. Int. J. Cancer. 2006;119:1837–1842. doi: 10.1002/ijc.22046. PubMed DOI

Fodde R. The APC gene in colorectal cancer. Eur. J. Cancer. 2002;38:867–871. doi: 10.1016/S0959-8049(02)00040-0. PubMed DOI

Kim S., Jeong S. Mutation hotspots in the β-catenin gene: Lessons from the human cancer genome databases. Mol. Cells. 2019 doi: 10.14348/molcells.2018.0436. PubMed DOI PMC

Anvarian Z., Nojima H., van Kappel E.C., Madl T., Spit M., Viertler M., Jordens I., Low T.Y., van Scherpenzeel R.C., Kuper I., et al. Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network. Nat. Struct. Mol. Biol. 2016 doi: 10.1038/nsmb.3191. PubMed DOI

Foldynova-Trantirkova S., Sekyrova P., Tmejova K., Brumovska E., Bernatik O., Blankenfeldt W., Krejci P., Kozubik A., Dolezal T., Trantirek L., et al. Breast cancer-specific mutations in CK1epsilon inhibit Wnt/beta-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration. Breast Cancer Res. 2010;12:R30. doi: 10.1186/bcr2581. PubMed DOI PMC

Kaucka M., Plevova K., Pavlova S., Janovska P., Mishra A., Verner J., Prochazkova J., Krejci P., Kotaskova J., Ovesna P., et al. The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of b-lymphocyte migration. Cancer Res. 2013;73:1491–1501. doi: 10.1158/0008-5472.CAN-12-1752. PubMed DOI

Baskar S., Kwong K.Y., Hofer T., Levy J.M., Kennedy M.G., Lee E., Staudt L.M., Wilson W.H., Wiestner A., Rader C. Unique cell surface expression of receptor tyrosine kinase ROR1 in human B-cell chronic lymphocytic leukemia. Clin. Cancer Res. 2008;14:396–404. doi: 10.1158/1078-0432.CCR-07-1823. PubMed DOI

Janovska P., Verner J., Kohoutek J., Bryjova L., Gregorova M., Dzimkova M., Skabrahova H., Radaszkiewicz T., Ovesna P., Vondalova Blanarova O., et al. Casein Kinase 1 is a Therapeutic Target in Chronic Lymphocytic Leukemia. Blood. 2018 doi: 10.1182/blood-2017-05-786947. PubMed DOI

Wang L., Shalek A.K., Lawrence M., Ding R., Gaublomme J.T., Pochet N., Stojanov P., Sougnez C., Shukla S.A., Stevenson K.E., et al. Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL. Blood. 2014;124 doi: 10.1182/blood-2014-01-552067. PubMed DOI PMC

Khan A.S., Hojjat-Farsangi M., Daneshmanesh A.H., Hansson L., Kokhaei P., Österborg A., Mellstedt H., Moshfegh A. Dishevelled proteins are significantly upregulated in chronic lymphocytic leukaemia. Tumour Biol. 2016 doi: 10.1007/s13277-016-5039-5. PubMed DOI

Cong F., Schweizer L., Varmus H. Casein kinase Iepsilon modulates the signaling specificities of dishevelled. Mol. Cell Biol. 2004;24:2000–2011. doi: 10.1128/MCB.24.5.2000-2011.2004. PubMed DOI PMC

Gao Z.H., Seeling J.M., Hill V., Yochum A., Virshup D.M. Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complex. Proc. Natl. Acad. Sci. USA. 2002;99:1182–1187. doi: 10.1073/pnas.032468199. PubMed DOI PMC

Polakis P. The many ways of Wnt in cancer. Curr. Opin. Genet. Dev. 2007;17:45–51. doi: 10.1016/j.gde.2006.12.007. PubMed DOI

Okamura H., Garcia-Rodriguez C., Martinson H., Qin J., Virshup D.M., Rao A. A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol. Cell Biol. 2004;24:4184–4195. doi: 10.1128/MCB.24.10.4184-4195.2004. PubMed DOI PMC

Utz A.C., Hirner H., Blatz A., Hillenbrand A., Schmidt B., Deppert W., Henne-Bruns D., Fischer D., Thal D.R., Leithäuser F., et al. Analysis of cell type-specific expression of CK1 epsilon in various tissues of young adult BALB/c Mice and in mammary tumors of SV40 T-Ag-transgenic mice. J. Histochem. Cytochem. 2010;58:1–15. doi: 10.1369/jhc.2009.954628. PubMed DOI PMC

Grainger S., Traver D., Willert K. Wnt Signaling in Hematological Malignancies. Prog. Mol. Biol. Transl. Sci. 2018;153:321–341. doi: 10.1016/bs.pmbts.2017.11.002. PubMed DOI PMC

Staal F.J.T., Chhatta A., Mikkers H. Caught in a Wnt storm: Complexities of Wnt signaling in hematopoiesis. Exp. Hematol. 2016;44:451–457. doi: 10.1016/j.exphem.2016.03.004. PubMed DOI

Janovská P., Bryja V. Wnt signalling pathways in chronic lymphocytic leukaemia and B-cell lymphomas. Br. J. Pharmacol. 2017;174:4701–4715. doi: 10.1111/bph.13949. PubMed DOI PMC

Cozza G., Pinna L.A. Casein kinases as potential therapeutic targets. Expert Opin. Ther. Targets. 2015;20:319–340. doi: 10.1517/14728222.2016.1091883. PubMed DOI

Cunningham P.S., Ahern S.A., Smith L.C., da Silva Santos C.S., Wager T.T., Bechtold D.A. Targeting of the circadian clock via CK1δ/ϵ to improve glucose homeostasis in obesity. Sci. Rep. 2016 doi: 10.1038/srep29983. PubMed DOI PMC

Arey R., McClung C.A. An inhibitor of casein kinase 1 ε/δ partially normalizes the manic-like behaviors of the ClockΔ19 mouse. Behav. Pharmacol. 2012;23:392–396. doi: 10.1097/FBP.0b013e32835651fd. PubMed DOI PMC

Perreau-Lenz S., Vengeliene V., Noori H.R., Merlo-Pich E.V., Corsi M.A., Corti C., Spanagel R. Inhibition of the casein-kinase-1-ε/δ/prevents relapse-like alcohol drinking. Neuropsychopharmacology. 2012;37:2121–2131. doi: 10.1038/npp.2012.62. PubMed DOI PMC

Wager T.T., Chandrasekaran R.Y., Bradley J., Rubitski D., Berke H., Mente S., Butler T., Doran A., Chang C., Fisher K., et al. Casein kinase 1δ/ε inhibitor PF-5006739 attenuates opioid drug-seeking behavior. ACS Chem. Neurosci. 2014 doi: 10.1021/cn500201x. PubMed DOI

Rosenberg L.H., Lafitte M., Quereda V., Grant W., Chen W., Bibian M., Noguchi Y., Fallahi M., Yang C., Chang J.C., et al. Therapeutic targeting of casein kinase 1δ in breast cancer. Sci. Transl. Med. 2015;7:318ra202. doi: 10.1126/scitranslmed.aac8773. PubMed DOI PMC

Liu C., Witt L., Ianes C., Bischof J., Bammert M.T., Baier J., Kirschner S., Henne-Bruns D., Xu P., Kornmann M., et al. Newly developed CK1-specific inhibitors show specifically stronger effects on ck1 mutants and colon cancer cell lines. Int. J. Mol. Sci. 2019;20:6184. doi: 10.3390/ijms20246184. PubMed DOI PMC

Rena G., Bain J., Elliott M., Cohen P. D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep. 2004;5:60–65. doi: 10.1038/sj.embor.7400048. PubMed DOI PMC

Mashhoon N., DeMaggio A.J., Tereshko V., Bergmeier S.C., Egli M., Hoekstra M.F., Kuret J. Crystal structure of a conformation-selective casein kinase-1 inhibitor. J. Biol. Chem. 2000 doi: 10.1074/jbc.M001713200. PubMed DOI

Brockschmidt C., Hirner H., Huber N., Eismann T., Hillenbrand A., Giamas G., Radunsky B., Ammerpohl O., Bohm B., Henne-Bruns D., et al. Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo. Gut. 2008;57:799–806. doi: 10.1136/gut.2007.123695. PubMed DOI

Toyoshima M., Howie H.L., Imakura M., Walsh R.M., Annis J.E., Chang A.N., Frazier J., Chau B.N., Loboda A., Linsley P.S., et al. Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc. Natl. Acad. Sci. USA. 2012;109:9545–9550. doi: 10.1073/pnas.1121119109. PubMed DOI PMC

Cheong J.K., Nguyen T.H., Wang H., Tan P., Voorhoeve P.M., Lee S.H., Virshup D.M. IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1delta/varepsilon and Wnt/beta-catenin independent inhibition of mitotic spindle formation. Oncogene. 2011;30:2558–2569. doi: 10.1038/onc.2010.627. PubMed DOI PMC

Anastassiadis T., Deacon S.W., Devarajan K., Ma H., Peterson J.R. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol. 2011 doi: 10.1038/nbt.2017. PubMed DOI PMC

Walton K.M., Fisher K., Rubitski D., Marconi M., Meng Q.-J., Adams J., Bass M., Chandrasekaran R., Butler T., Griffor M., et al. Selective Inhibition of Casein Kinase 1ε Minimally Alters Circadian Clock Period. J. Pharmacol. Exp. Ther. 2009;330:430–439. doi: 10.1124/jpet.109.151415. PubMed DOI

Meng Q.-J., Maywood E.S., Bechtold D.A., Lu W.-Q., Li J., Gibbs J.E., Dupré S.M., Chesham J.E., Rajamohan F., Knafels J., et al. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc. Natl. Acad. Sci. USA. 2010;107:15240–15245. doi: 10.1073/pnas.1005101107. PubMed DOI PMC

Badura L., Swanson T., Adamowicz W., Adams J., Cianfrogna J., Fisher K., Holland J., Kleiman R., Nelson F., Reynolds L., et al. An inhibitor of casein kinase I epsilon induces phase delays in circadian rhythms under free-running and entrained conditions. J. Pharmacol. Exp. Ther. 2007;322:730–738. doi: 10.1124/jpet.107.122846. PubMed DOI

Deng C., Lipstein M.R., Scotto L., Jirau Serrano X.O., Mangone M.A., Li S., Vendome J., Hao Y., Xu X., Deng S.X., et al. Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kdelta and CK1epsilon in hematological malignancies. Blood. 2017;129:88–99. doi: 10.1182/blood-2016-08-731240. PubMed DOI PMC

Huang H., Acquaviva L., Berry V., Bregman H., Chakka N., O’Connor A., Dimauro E.F., Dovey J., Epstein O., Grubinska B., et al. Structure-based design of potent and selective CK1γ inhibitors. ACS Med. Chem. Lett. 2012 doi: 10.1021/ml300278f. PubMed DOI PMC

Zhang T., Davidson-Moncada J.K., Mukherjee P., Furman R.R., Bhavsar E., Chen Z., Hakimpour P., Papavasiliou N., Tam W. MicroRNA-155 regulates casein kinase 1 gamma 2: A potential pathogenetic role in chronic lymphocytic leukemia. Blood Cancer J. 2017 doi: 10.1038/bcj.2017.80. PubMed DOI PMC

Hallek M. Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am. J. Hematol. 2019;94:1266–1287. doi: 10.1002/ajh.25595. PubMed DOI

Sant M., Allemani C., Tereanu C., De Angelis R., Capocaccia R., Visser O., Marcos-Gragera R., Maynadié M., Simonetti A., Lutz J.-M., et al. Incidence of hematologic malignancies in Europe by morphologic subtype: Results of the HAEMACARE project. Blood. 2010;116:3724–3734. doi: 10.1182/blood-2010-05-282632. PubMed DOI

Janovska P., Poppova L., Plevova K., Plesingerova H., Behal M., Kaucka M., Ovesna P., Hlozkova M., Borsky M., Stehlikova O., et al. Autocrine signaling by Wnt-5a deregulates chemotaxis of leukemic cells and predicts clinical outcome in chronic lymphocytic leukemia. Clin. Cancer Res. 2016;22:459–469. doi: 10.1158/1078-0432.CCR-15-0154. PubMed DOI PMC

Plešingerová H., Janovská P., Mishra A., Smyčková L., Poppová L., Libra A., Plevová K., Ovesná P., Radová L., Doubek M., et al. Expression of COBLL1 encoding novel ROR1 binding partner is robust predictor of survival in chronic lymphocytic leukemia. Haematologica. 2018;103:313–324. doi: 10.3324/haematol.2017.178699. PubMed DOI PMC

Daneshmanesh A.H., Mikaelsson E., Jeddi-Tehrani M., Bayat A.A., Ghods R., Ostadkarampour M., Akhondi M., Lagercrantz S., Larsson C., Osterborg A., et al. Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy. Int. J. Cancer. 2008;123:1190–1195. doi: 10.1002/ijc.23587. PubMed DOI

Fukuda T., Chen L., Endo T., Tang L., Lu D., Castro J.E., Widhopf G.F., Rassenti L.Z., Cantwell M.J., Prussak C.E., et al. Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a. Proc. Natl. Acad. Sci. USA. 2008;105:3047–3052. doi: 10.1073/pnas.0712148105. PubMed DOI PMC

Daneshmanesh A.H., Porwit A., Hojjat-Farsangi M., Jeddi-Tehrani M., Tamm K.P., Grandér D., Lehmann S., Norin S., Shokri F., Rabbani H., et al. Orphan receptor tyrosine kinases ROR1 and ROR2 in hematological malignancies. Leuk. Lymphoma. 2013;8194:843–850. doi: 10.3109/10428194.2012.731599. PubMed DOI

Karvonen H., Chiron D., Niininen W., Ek S., Jerkeman M., Moradi E., Nykter M., Heckman C.A., Kallioniemi O., Murumägi A., et al. Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma. Blood Adv. 2017;1:2257–2268. doi: 10.1182/bloodadvances.2017010215. PubMed DOI PMC

Campo E., Raffeld M., Jaffe E.S. Mantle-cell lymphoma. Semin. Hematol. 1999;36:115–127. PubMed

Choi M.Y., Widhopf G.F., Wu C.C.N., Cui B., Lao F., Sadarangani A., Cavagnaro J., Prussak C., Carson D.A., Jamieson C., et al. Pre-clinical Specificity and Safety of UC-961, a First-In-Class Monoclonal Antibody Targeting ROR1. Clin. Lymphoma Myeloma Leuk. 2015;15:S167–S169. doi: 10.1016/j.clml.2015.02.010. PubMed DOI PMC

Berger C., Sommermeyer D., Hudecek M., Berger M., Balakrishnan A., Paszkiewicz P.J., Kosasih P.L., Rader C., Riddell S.R. Safety of Targeting ROR1 in Primates with Chimeric Antigen Receptor-Modified T Cells. Cancer Immunol. Res. 2015;3:206–216. doi: 10.1158/2326-6066.CIR-14-0163. PubMed DOI PMC

Liu X., Pu W., He H., Fan X., Zheng Y., Zhou J.K., Ma R., He J., Zheng Y., Wu K., et al. Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer. Cancer Lett. 2019 doi: 10.1016/j.canlet.2019.05.016. PubMed DOI

Fultang N., Illendula A., Chen B., Wu C., Jonnalagadda S., Baird N., Klase Z., Peethambaran B. Strictinin, a novel ROR1-inhibitor, represses triple negative breast cancer survival and migration via modulation of PI3K/AKT/GSK3ß activity. PLoS ONE. :2019. doi: 10.1371/journal.pone.0217789. PubMed DOI PMC

Daneshmanesh A.H., Hojjat-Farsangi M., Ghaderi A., Moshfegh A., Hansson L., Schultz J., Vågberg J., Byström S., Olsson E., Olin T., et al. A receptor tyrosine kinase ROR1 inhibitor (KAN0439834) induced significant apoptosis of pancreatic cells which was enhanced by erlotinib and ibrutinib. PLoS ONE. 2018 doi: 10.1371/journal.pone.0198038. PubMed DOI PMC

Mellstedt H., Ghaderi A., Aschan J., Mozaffari F., Moshfegh A., Sander B., Schultz J., Norin M., Olin T., Drakos E., et al. ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells. Blood. 2019 doi: 10.1182/blood-2019-129773. PubMed DOI PMC

Karvonen H., Perttilä R., Niininen W., Barker H., Ungureanu D. Targeting Wnt signaling pseudokinases in hematological cancers. Eur. J. Haematol. 2018 doi: 10.1111/ejh.13137. PubMed DOI

Zhang S., Chen L., Cui B., Chuang H.-Y., Yu J., Wang-Rodriguez J., Tang L., Chen G., Basak G.W., Kipps T.J. ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS ONE. 2012;7:e31127. doi: 10.1371/journal.pone.0031127. PubMed DOI PMC

Modak C., Bryant P. Casein Kinase I epsilon positively regulates the Akt pathway in breast cancer cell lines. Biochem. Biophys. Res. Commun. 2008;368:801–807. doi: 10.1016/j.bbrc.2008.02.001. PubMed DOI PMC

Kani S., Oishi I., Yamamoto H., Yoda A., Suzuki H., Nomachi A., Iozumi K., Nishita M., Kikuchi A., Takumi T., et al. The receptor tyrosine kinase Ror2 associates with and is activated by casein kinase Iepsilon. J. Biol. Chem. 2004 doi: 10.1074/jbc.M409039200. PubMed DOI

Kim J., Kim D.W., Chang W., Choe J., Kim J., Park C.-S., Song K., Lee I. Wnt5a is secreted by follicular dendritic cells to protect germinal center B cells via Wnt/Ca2+/NFAT/NF-κB-B cell lymphoma 6 signaling. J. Immunol. 2012;188:182–189. doi: 10.4049/jimmunol.1102297. PubMed DOI

Yu J., Chen L., Cui B., Widhopf G.F., II, Shen Z., Wu R., Zhang L., Zhang S., Briggs S.P., Kipps T.J. Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation. J. Clin. Investig. 2016;126:585–598. doi: 10.1172/JCI83535. PubMed DOI PMC

Hasan M.K., Yu J., Chen L., Cui B., Widhopf Ii G.F., Rassenti L., Shen Z., Briggs S.P., Kipps T.J. Wnt5a induces ROR1 to complex with HS1 to enhance migration of chronic lymphocytic leukemia cells. Leukemia. 2017;31:2615–2622. doi: 10.1038/leu.2017.133. PubMed DOI PMC

Hasan M.K., Yu J., Widhopf G.F., II, Rassenti L.Z., Chen L., Shen Z., Briggs S.P., Neuberg D.S., Kipps T.J. Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia. Blood. 2018;132:170–178. doi: 10.1182/blood-2017-12-819383. PubMed DOI PMC

Yu J., Chen L., Chen Y., Hasan M.K., Ghia E.M., Zhang L., Wu R., Rassenti L.Z., Widhopf G.F., Shen Z., et al. Wnt5a induces ROR1 to associate with 14-3-3ζ for enhanced chemotaxis and proliferation of chronic lymphocytic leukemia cells. Leukemia. 2017;31:2608–2614. doi: 10.1038/leu.2017.132. PubMed DOI PMC

Zhang Q., Wang H.Y., Liu X., Nunez-Cruz S., Jillab M., Melnikov O., Nath K., Glickson J., Wasik M.A. Cutting Edge: ROR1/CD19 Receptor Complex Promotes Growth of Mantle Cell Lymphoma Cells Independently of the B Cell Receptor–BTK Signaling Pathway. J. Immunol. 2019;203:2043–2048. doi: 10.4049/jimmunol.1801327. PubMed DOI PMC

Hasan M.K., Rassenti L., Widhopf G.F., Yu J., Kipps T.J. Wnt5a causes ROR1 to complex and activate cortactin to enhance migration of chronic lymphocytic leukemia cells. Leukemia. 2019 doi: 10.1038/s41375-018-0306-7. PubMed DOI PMC

Rudelius M., Pittaluga S., Nishizuka S., Pham T.H., Fend F., Jaffe E.S., Quintanilla-Martinez L., Raffeld M. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood. 2006;108:1668–1676. doi: 10.1182/blood-2006-04-015586. PubMed DOI PMC

Linke F., Zaunig S., Nietert M.M., VonBonin F., Lutz S., Dullin C., Janovská P., Beissbarth T., Alves F., Klapper W., et al. WNT5A: A motility-promoting factor in Hodgkin lymphoma. Oncogene. 2017;36:13–23. doi: 10.1038/onc.2016.183. PubMed DOI

Cui B., Chen L., Rassenti L.Z., Ghia E.M., Yu J., Zhang L., Neuberg D.S., Wierda W., Keating M., Rai K., et al. High-level expression of ROR1 associates with early disease progression in patients with chronic lymphocytic leukemia. Blood. 2015;126:1713. doi: 10.1182/blood.V126.23.1713.1713. DOI

Widhopf 2nd G.F., Cui B., Ghia E.M., Chen L., Messer K., Shen Z., Briggs S.P., Croce C.M., Kipps T.J. ROR1 can interact with TCL1 and enhance leukemogenesis in Emu-TCL1 transgenic mice. Proc. Natl. Acad. Sci. USA. 2014;111:793–798. doi: 10.1073/pnas.1308374111. PubMed DOI PMC

Wu Q.-L. Dysregulation of Frizzled 6 is a critical component of Bcell leukemogenesis in a mouse model of chronic lymphocytic leukemia. Blood. 2009 doi: 10.1182/blood. PubMed DOI PMC

Kaucká M., Petersen J., Janovská P., Radaszkiewicz T., Smyčková L., Daulat A.M., Borg J.P., Schulte G., Bryja V. Asymmetry of VANGL2 in migrating lymphocytes as a tool to monitor activity of the mammalian WNT/planar cell polarity pathway. Cell Commun. Signal. 2015;13:2. doi: 10.1186/s12964-014-0079-1. PubMed DOI PMC

Hartmann E.M., Rudelius M., Burger J.A., Rosenwald A. CCL3 chemokine expression by chronic lymphocytic leukemia cells orchestrates the composition of the microenvironment in lymph node infiltrates. Leuk. Lymphoma. 2016;57:563–571. doi: 10.3109/10428194.2015.1068308. PubMed DOI PMC

Burris 3rd H.A., Flinn I.W., Patel M.R., Fenske T.S., Deng C., Brander D.M., Gutierrez M., Essell J.H., Kuhn J.G., Miskin H.P., et al. Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: An open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19:486–496. doi: 10.1016/S1470-2045(18)30082-2. PubMed DOI

Lunning M., Vose J., Nastoupil L., Fowler N., Burger J.A., Wierda W.G., Schreeder M.T., Siddiqi T., Flowers C.R., Cohen J.B., et al. Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2019;134:1811–1820. doi: 10.1182/blood.2019002118. PubMed DOI PMC

Davids M.S., Kim H.T., Nicotra A., Savell A., Francoeur K., Hellman J.M., Bazemore J., Miskin H.P., Sportelli P., Stampleman L., et al. Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: A multicentre phase 1-1b study. Lancet Haematol. 2019;6:e38–e47. doi: 10.1016/S2352-3026(18)30196-0. PubMed DOI PMC

Maharaj K., Powers J.J., Achille A., Mediavilla-Varela M., Gamal W., Burger K.L., Fonseca R., Jiang K., Miskin H.P., Maryanski D., et al. The dual PI3Kdelta/CK1epsilon inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. Blood Adv. 2020;4:3072–3084. doi: 10.1182/bloodadvances.2020001800. PubMed DOI PMC

Shin S., Wolgamott L., Roux P.P., Yoon S.O. Casein kinase 1epsilon promotes cell proliferation by regulating mRNA translation. Cancer Res. 2014;74:201–211. doi: 10.1158/0008-5472.CAN-13-1175. PubMed DOI

van Loosdregt J., Fleskens V., Tiemessen M.M., Mokry M., van Boxtel R., Meerding J., Pals C.E., Kurek D., Baert M.R., Delemarre E.M., et al. Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity. 2013;39:298–310. doi: 10.1016/j.immuni.2013.07.019. PubMed DOI

Yu J., Chen L., Cui B., Wu C., Choi M.Y., Chen Y., Zhang L., Rassenti L.Z., Widhopf Ii G.F., Kipps T.J. Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib. Leukemia. 2017;31:1333–1339. doi: 10.1038/leu.2016.368. PubMed DOI PMC

Nastoupil L.J., Lunning M.A., Vose J.M., Schreeder M.T., Siddiqi T., Flowers C.R., Cohen J.B., Burger J.A., Wierda W.G., O’Brien S., et al. Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: A phase 1 dose escalation and expansion trial. Lancet Haematol. 2019;6:e100–e109. doi: 10.1016/S2352-3026(18)30216-3. PubMed DOI

Hellström-Lindberg E., Tobiasson M., Greenberg P. Myelodysplastic syndromes: Moving towards personalized management. Haematologica. 2020 doi: 10.3324/haematol.2020.248955. PubMed DOI PMC

Estey E.H. Acute myeloid leukemia: 2019 update on risk-stratification and management. Am. J. Hematol. 2018 doi: 10.1002/ajh.25214. PubMed DOI

Heuser M., Ofran Y., Boissel N., Brunet Mauri S., Craddock C., Janssen J., Wierzbowska A., Buske C. Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2020 doi: 10.1016/j.annonc.2020.02.018. PubMed DOI

Ogawa S. Genetics of MDS. Blood. 2019 doi: 10.1182/blood-2018-10-844621. PubMed DOI PMC

Short N.J., Konopleva M., Kadia T.M., Borthakur G., Ravandi F., DiNardo C.D., Daver N. Advances in the treatment of acute myeloid leukemia: New drugs and new challenges. Cancer Discov. 2020;10:506–525. doi: 10.1158/2159-8290.CD-19-1011. PubMed DOI

Maynadié M., Girodon F., Manivet-Janoray I., Mounier M., Mugneret F., Bailly F., Favre B., Caillot D., Petrella T., Flesch M., et al. Twenty-five years of epidemiological recording on myeloid malignancies: Data from the specialized registry of hematologic malignancies of côte d’or (Burgundy, France) Haematologica. 2011 doi: 10.3324/haematol.2010.026252. PubMed DOI PMC

Schneider R.K., Ademà V., Heckl D., Järås M., Mallo M., Lord A.M., Chu L.P., McConkey M.E., Kramann R., Mullally A., et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell. 2014 doi: 10.1016/j.ccr.2014.08.001. PubMed DOI PMC

Krönke J., Fink E.C., Hollenbach P.W., MacBeth K.J., Hurst S.N., Udeshi N.D., Chamberlain P.P., Mani D.R., Man H.W., Gandhi A.K., et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015 doi: 10.1038/nature14610. PubMed DOI PMC

Ebert B.L. Molecular Dissection of the 5q Deletion in Myelodysplastic Syndrome. Semin. Oncol. 2011 doi: 10.1053/j.seminoncol.2011.04.010. PubMed DOI PMC

Haase D., Germing U., Schanz J., Pfeilstöcker M., Nösslinger T., Hildebrandt B., Kundgen A., Lübbert M., Kunzmann R., Giagounidis A.A.N., et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: Evidence from a core dataset of 2124 patients. Blood. 2007 doi: 10.1182/blood-2007-03-082404. PubMed DOI

Hasserjian R.P. Myelodysplastic Syndrome Updated. Pathobiology. 2019 doi: 10.1159/000489702. PubMed DOI

Li L., Sheng Y., Li W., Hu C., Mittal N., Tohyama K., Seba A., Zhao Y.Y., Ozer H., Zhu T., et al. β-catenin is a candidate therapeutic target for myeloid neoplasms with del(5q) Cancer Res. 2017 doi: 10.1158/0008-5472.CAN-17-0202. PubMed DOI PMC

Järås M., Miller P.G., Chu L.P., Puram R.V., Fink E.C., Schneider R.K., Al-Shahrour F., Peña P., Breyfogle L.J., Hartwell K.A., et al. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. J. Exp. Med. 2014;211:605–612. doi: 10.1084/jem.20131033. PubMed DOI PMC

Huart A.S., MacLaine N.J., Meek D.W., Hupp T.R. CK1α plays a central role in mediating MDM2 control of p53 and E2F-1 protein stability. J. Biol. Chem. 2009 doi: 10.1074/jbc.M109.052647. PubMed DOI PMC

Wei X. Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding. Proc. Natl. Acad. Sci. USA. 2016 doi: 10.1073/pnas.1603838113. PubMed DOI PMC

Wu S., Chen L., Becker A., Schonbrunn E., Chen J. Casein Kinase 1 Regulates an MDMX Intramolecular Interaction To Stimulate p53 Binding. Mol. Cell. Biol. 2012 doi: 10.1128/MCB.00851-12. PubMed DOI PMC

Elyada E., Pribluda A., Goldstein R.E., Morgenstern Y., Brachya G., Cojocaru G., Snir-Alkalay I., Burstain I., Haffner-Krausz R., Jung S., et al. CKIα ablation highlights a critical role for p53 in invasiveness control. Nature. 2011;470:409–413. doi: 10.1038/nature09673. PubMed DOI

Khalaileh A., Dreazen A., Khatib A., Apel R., Swisa A., Kidess-Bassir N., Maitra A., Meyuhas O., Dor Y., Zamir G. Phosphorylation of ribosomal protein S6 attenuates DNA damage and tumor suppression during development of pancreatic cancer. Cancer Res. 2013 doi: 10.1158/0008-5472.CAN-12-2014. PubMed DOI

Takam Kamga P., Dal Collo G., Cassaro A., Bazzoni R., Delfino P., Adamo A., Bonato A., Carbone C., Tanasi I., Bonifacio M., et al. Small Molecule Inhibitors of Microenvironmental Wnt/β-Catenin Signaling Enhance the Chemosensitivity of Acute Myeloid Leukemia. Cancers. 2020;12:2696. doi: 10.3390/cancers12092696. PubMed DOI PMC

Wang Y., Krivtsov A.V., Sinha A.U., North T.E., Goessling W., Feng Z., Zon L.I., Armstrong S.A. The wnt/β-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010 doi: 10.1126/science.1186624. PubMed DOI PMC

Yeung J., Esposito M.T., Gandillet A., Zeisig B.B., Griessinger E., Bonnet D., So C.W.E. β-Catenin Mediates the Establishment and Drug Resistance of MLL Leukemic Stem Cells. Cancer Cell. 2010 doi: 10.1016/j.ccr.2010.10.032. PubMed DOI

Miller P.G., Al-Shahrour F., Hartwell K.A., Chu L.P., Järås M., Puram R.V., Puissant A., Callahan K.P., Ashton J., McConkey M.E., et al. InVivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling. Cancer Cell. 2013 doi: 10.1016/j.ccr.2013.05.004. PubMed DOI PMC

Gruszka A.M., Valli D., Alcalay M. Wnt Signalling in Acute Myeloid Leukaemia. Cells. 2019;8:1403. doi: 10.3390/cells8111403. PubMed DOI PMC

Liu C., Li Y., Semenov M., Han C., Baeg G.H., Tan Y., Zhang Z., Lin X., He X. Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002 doi: 10.1016/S0092-8674(02)00685-2. PubMed DOI

Kadia T.M., Jain P., Ravandi F., Garcia-Manero G., Andreef M., Takahashi K., Borthakur G., Jabbour E., Konopleva M., Daver N.G., et al. TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. Cancer. 2016 doi: 10.1002/cncr.30203. PubMed DOI PMC

Lehmann S., Bykov V.J., Ali D., Andrén O., Cherif H., Tidefelt U., Uggla B., Yachnin J., Juliusson G., Moshfegh A., et al. Targeting p53 in vivo: A first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J. Clin. Oncol. 2012 doi: 10.1200/JCO.2011.40.7783. PubMed DOI

Maslah N., Salomao N., Drevon L., Verger E., Partouche N., Ly P., Aubin P., Naoui N., Schlageter M.H., Bally C., et al. Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2020 doi: 10.3324/haematol.2019.218453. PubMed DOI PMC

Matsuoka A., Tochigi A., Kishimoto M., Nakahara T., Kondo T., Tsujioka T., Tasaka T., Tohyama Y., Tohyama K. Lenalidomide induces cell death in an MDS-derived cell line with deletion of chromosome 5q by inhibition of cytokinesis. Leukemia. 2010 doi: 10.1038/leu.2009.296. PubMed DOI

Chen Y., Borthakur G. Lenalidomide as a novel treatment of acute myeloid leukemia. Expert Opin. Investig. Drugs. 2013 doi: 10.1517/13543784.2013.758712. PubMed DOI

List A., Dewald G., Bennett J., Giagounidis A., Raza A., Feldman E., Powell B., Greenberg P., Thomas D., Stone R., et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N. Engl. J. Med. 2006 doi: 10.1056/NEJMoa061292. PubMed DOI

Pellagatti A., Jädersten M., Forsblom A.M., Cattan H., Christensson B., Emanuelsson E.K., Merup M., Nilsson L., Samuelsson J., Sander B., et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc. Natl. Acad. Sci. USA. 2007 doi: 10.1073/pnas.0610477104. PubMed DOI PMC

Xie C.H., Wei M., Yang F.Y., Wu F.Z., Chen L., Wang J.K., Liu Q., Huang J.X. Efficacy and safety of lenalidomide for thtreatment of acute myeloid leukemia: A systematic review and meta-analysis. Cancer Manag. Res. 2018 doi: 10.2147/CMAR.S168610. PubMed DOI PMC

Chellappa S., Kushekhar K., Munthe L.A., Tjonnfjord G.E., Aandahl E.M., Okkenhaug K., Tasken K. The PI3K p110delta Isoform Inhibitor Idelalisib Preferentially Inhibits Human Regulatory T Cell Function. J. Immunol. 2019;202:1397–1405. doi: 10.4049/jimmunol.1701703. PubMed DOI

Bibian M. Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties. Bioorg. Med. Chem. Lett. 2013;23:4374–4380. doi: 10.1016/j.bmcl.2013.05.075. PubMed DOI PMC

Morgenstern Y., Das Adhikari U., Ayyash M., Elyada E., Tóth B., Moor A., Itzkovitz S., Ben-Neriah Y. Casein kinase 1-epsilon or 1-delta required for Wnt-mediated intestinal stem cell maintenance. EMBO J. 2017;36:3046–3061. doi: 10.15252/embj.201696253. PubMed DOI PMC

Sen M., Chamorro M., Reifert J., Corr M., Carson D.A. Blockade of Wnt-5A/frizzled 5 signaling inhibits rheumatoid synoviocyte activation. Arthritis Rheum. 2001;44:772–781. doi: 10.1002/1529-0131(200104)44:4<772::AID-ANR133>3.0.CO;2-L. PubMed DOI

He T., Wu D., He L., Wang X., Yang B., Li S., Chen Y., Wang K., Chen R., Liu B., et al. Casein kinase 1 epsilon facilitates cartilage destruction in osteoarthritis through JNK pathway. FASEB J. 2020 doi: 10.1096/fj.201902672R. PubMed DOI

Reischl J., Schwenke S., Beekman J.M., Stürzebecher J., Mrowietz U., Heubach J.F. Increased expression of Wnt5a in psoriatic plaques. J. Investig. Dermatol. 2007;127:163–169. doi: 10.1038/sj.jid.5700488. PubMed DOI

Choi E.Y., Park H.H., Kim H., Kim H.N., Kim I., Jeon S., Kim W., Bae J.-S., Lee W. Wnt5a and Wnt11 as acute respiratory distress syndrome biomarkers for SARS-CoV-2 patients. Eur. Respir. J. 2020 doi: 10.1183/13993003.01531-2020. PubMed DOI PMC

Zyss D., Ebrahimi H., Gergely F. Casein kinase I delta controls centrosome positioning during T cell activation. J. Cell Biol. 2011;195:781–797. doi: 10.1083/jcb.201106025. PubMed DOI PMC

Hu Y., Song W., Cirstea D., Lu D., Munshi N.C., Anderson K.C. CSNK1α1 mediates malignant plasma cell survival. Leukemia. 2015;29:474–482. doi: 10.1038/leu.2014.202. PubMed DOI PMC

Manni S., Carrino M., Manzoni M., Gianesin K., Nunes S.C., Costacurta M., Tubi L.Q., Macaccaro P., Taiana E., Cabrelle A., et al. Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and ß-catenin survival signaling pathways. Oncotarget. 2017 doi: 10.18632/oncotarget.14654. PubMed DOI PMC

Carrino M., Quotti Tubi L., Fregnani A., Canovas Nunes S., Barilà G., Trentin L., Zambello R., Semenzato G., Manni S., Piazza F. Prosurvival autophagy is regulated by protein kinase CK1 alpha in multiple myeloma. Cell Death Discov. 2019 doi: 10.1038/s41420-019-0179-1. PubMed DOI PMC

Cheong J.K., Zhang F., Chua P.J., Bay B.H., Thorburn A., Virshup D.M. Casein kinase 1α-dependent feedback loop controls autophagy in RAS-driven cancers. J. Clin. Investig. 2015 doi: 10.1172/JCI78018. PubMed DOI PMC

Splice variants of CK1α and CK1α-like: Comparative analysis of subcellular localization, kinase activity, and function in the Wnt signaling pathway

Intestinal Paneth cell differentiation relies on asymmetric regulation of Wnt signaling by Daam1/2

Role of casein kinase 1 in the amoeboid migration of B-cell leukemic and lymphoma cells: A quantitative live imaging in the confined environment