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4 - Cell cycle regulation and myeloma precursor cells

from Section 2 - Biological basis for targeted therapies in myeloma

Published online by Cambridge University Press:  18 December 2013

By
John Quinn  and
Kwee L. Yong
Edited by
Stephen A. Schey ,
Kwee L. Yong ,
Robert Marcus  and
Kenneth C. Anderson
Stephen A. Schey
Affiliation:
Department of Haematology, King’s College Hospital, London
Kwee L. Yong
Affiliation:
Department of Haematology, University College Hospital, London
Robert Marcus
Affiliation:
Department of Haematology, King’s College Hospital, London
Kenneth C. Anderson
Affiliation:
Dana-Farber Cancer Institute, Boston
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Summary

Introduction

Unlike normal terminally differentiated plasma cells, MM cells are capable of self-renewal and proliferation. The direct impact of MM genetics on the expression and function of cell cycle proteins has provided the starting point for recent studies investigating the manner in which neoplastic plasma cells are able to bypass the cell cycle exit that is a pre-requisite for terminal plasma cell differentiation. The search for tumor-initiating “stem” or “progenitor” cells is a current area of intense activity, and multiple myeloma, with its pre-malignant phase (MGUS), its derivation from an memory B cell compartment, and the (sometimes long) periods of disease quiescence termed the “plateau phase” offers unique opportunities to test certain hypotheses regarding these elusive cells. This chapter summarizes the current state of knowledge regarding cell cycle dysregulation in MM, and the existence and properties of myeloma precursor cells.

Cell cycle control

The mammalian cell cycle is tightly regulated through “checkpoints” to ensure that the cell enters S-phase undamaged. The transition between G1 and S-phase is regulated by the interaction between the major G1 cyclins – the D-type cyclins and the cyclin-dependent kinases (CDKs). The three D-type cyclins (D1, D2 and D3) control entry to the cell cycle and are usually induced in response to mitogens i.e. micro-environmental cytokines. D-type cyclins then bind to and activate CDK4 and -6 and these complexes phosphorylate retinoblastoma protein (phospho-pRb), thus allowing S-phase entry by releasing the E2F transcription factors which regulate genes controlling DNA synthesis[1] (Figure 4.1).

Type
Chapter
Information
Myeloma
Pathology, Diagnosis, and Treatment
 , pp. 39 - 47
Publisher: Cambridge University Press
Print publication year: 2013

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References

Sherr, C. J.D-type cyclins. Trends Biochem. Sci. 1995;20:187–90.CrossRefGoogle ScholarPubMed
Cheng, M., Olivier, P., Diehl, J. A. et al. The p21Cip1 and p27Kip1 CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J. 1999;18:1571–83.CrossRefGoogle Scholar
Sherr, C. J., Roberts, J. M.CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Development 1999;13:1501–12.CrossRefGoogle ScholarPubMed
Bergsagel, P. L., Kuehl, W. M., Zhan, F. et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 2005;106:296–303.CrossRefGoogle ScholarPubMed
Zhan, F., Huang, Y., Colla, S. et al. The molecular classification of multiple myeloma. Blood 2006;108:2020–8.CrossRefGoogle ScholarPubMed
Kuehl, W. M., Bergsagel, P. L. Early genetic events provide the basis for a clinical classification of multiple myeloma. ASH Education Program Book 2005(1):346–52.
Bergsagel, P. L., Kuehl, W. M.Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma. Immunological Reviews, 2003;194:96–104.CrossRefGoogle ScholarPubMed
Bergsagel, P. L., Kuehl, W. M.Chromosome translocations in multiple myeloma. Oncogene, 2001;20:5611–22.CrossRefGoogle ScholarPubMed
Chng, W. J., Glebov, O., Bergsagel, P. L., Kuehl, W. M.Genetic events in the pathogenesis of multiple myeloma. Best Practice Res. Clin. Haematol. 2007;20:571–96.CrossRefGoogle ScholarPubMed
Ely, S., Di Liberto, M., Niesvizky, R. et al. Mutually exclusive cyclin-dependent kinase 4/cyclin D1 and cyclin-dependent kinase 6/cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation in multiple myeloma. Cancer Research 2005;65:11;345–53.CrossRefGoogle ScholarPubMed
Glassford, J., Rabin, N., Lam, E. W. F., Yong, K. L.Functional regulation of D-type cyclins by insulin-like growth factor-I and serum in multiple myeloma cells. Br. J. Haematol. 2007;139:243–54.CrossRefGoogle ScholarPubMed
Quinn, J., Glassford, J., Percy, L. et al. APRIL promotes cell-cycle progression in primary multiple myeloma cells: influence of D-type cyclin group and translocation status. Blood 2011;117:890–901.CrossRefGoogle ScholarPubMed
Hurt, E. M., Wiestner, A., Rosenwald, A. et al. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell 2004;5:191–9.CrossRefGoogle ScholarPubMed
Morito, N., Yoh, K., Maeda, A. et al. A novel transgenic mouse model of the human multiple myeloma chromosomal translocation t(14;16)(q32;q23). Cancer Research 2011;71(2):339–48.CrossRefGoogle Scholar
Lesage, D., Troussard, X., Sola, B.The enigmatic role of cyclin D1 in multiple myeloma. Int. J. Cancer 2005;115(2):171–6.CrossRefGoogle ScholarPubMed
Fonseca, R., Blood, E. A., Oken, M. M. et al. Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood 2002;99(10):3735–41.CrossRefGoogle Scholar
Jirawatnotai, S., Hu, Y., Michowski, W. et al. A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 2011;474(7350):230–4.CrossRefGoogle ScholarPubMed
Martinez-Garcia, E., Popovic, R., Min, D. J. et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 2011;117(1):211–20.CrossRefGoogle Scholar
Pei, H., Zhang, L., Luo, K. et al. MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 2011;470(7332):124–8.CrossRefGoogle ScholarPubMed
Zingone, A., Cultraro, C. M., Shin, D. M. et al. Ectopic expression of wild-type FGFR3 cooperates with MYC to accelerate development of B-cell lineage neoplasms. Leukemia 2010;24(6):1171–8.CrossRefGoogle ScholarPubMed
Leone, P. E., Walker, B. A., Jenner, M. W. et al. Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clinical Cancer Research 2008;14(19):6033–41.CrossRefGoogle ScholarPubMed
Kulkarni, M. S., Daggett, J. L., Bender, T. P. et al. Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis. Leukemia 2002;16(1):127–34.CrossRefGoogle ScholarPubMed
Dib, A., Peterson, T. R., Raducha-Grace, L. et al. Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression. Cell Div. 2006;1:23.CrossRefGoogle ScholarPubMed
Streetly, M. J., Maharaj, L., Joel, S. et al. GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. Blood, 2010;115:3939–48.CrossRefGoogle ScholarPubMed
Mandl-Weber, S., Meinel, F. G., Jankowsky, R. et al. The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Br. J. Haematol. 2010;149:518–28.CrossRefGoogle ScholarPubMed
Hanamura, I., Stewart, J. P., Huang, Y. et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 2006;108(5):1724–32.CrossRefGoogle ScholarPubMed
Zhan, F., Colla, S., Wu, X. et al. CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood 2007;109(11):4995–5001.CrossRefGoogle ScholarPubMed
Ludwig, C. U., Durie, B. G. M., Salmon, S. E., Moon, T. E.Tumor growth stimulation in vitro by interferons. Eur. J. Cancer Clinical Oncol. 1983;19:1625–32.CrossRefGoogle ScholarPubMed
Jelinek, D. F., Aagaard-Tillery, K. M., Arendt, B. K. et al. Differential human multiple myeloma cell line responsiveness to interferon-alpha. Analysis of transcription factor activation and interleukin 6 receptor expression. J. Clin. Invest. 1997;99:447–56.CrossRefGoogle ScholarPubMed
Arora, T., Jelinek, D. F.Differential myeloma cell responsiveness to interferon-alpha correlates with differential induction of p19INK4d and cyclin D2 expression. J. Biol. Chem. 1998;273:11 799–805.CrossRefGoogle Scholar
Glassford, J., Kassen, D., Quinn, J. et al. Inhibition of cell cycle progression by dual phosphatidylinositol-3-kinase and mTOR blockade in cyclin D2 positive multiple myeloma bearing IgH translocations. Blood Cancer Journal, 2012;2:e50CrossRefGoogle ScholarPubMed
Lahti, J. M., Li, H., Kidd, V. J.Elimination of cyclin D1 in vertebrate cells leads to an altered cell cycle phenotype, which is rescued by overexpression of murine cyclins D1, D2, or D3 but not by a mutant cyclin D1. J. Biol. Chem. 1997;272:10;859–69.CrossRefGoogle ScholarPubMed
Tiedemann, R. E., Mao, X., Shi, C. X. et al. Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity. J. Clin. Invest. 2008;118:1750–64.Google ScholarPubMed
Klier, M., Anastasov, N., Hermann, A. et al. Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2. Leukemia 2008;22:2097–105.CrossRefGoogle ScholarPubMed
Tchakarska, G., Le Lan-Leguen, A., Roth, L., Sola, B.The targeting of the sole cyclin D1 is not adequate for mantle cell lymphoma and myeloma therapies. Haematologica 2009;94:1781–2.CrossRefGoogle Scholar
Baughn, L., Di Liberto, M., Wu, K. et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Research 2006;66:7661–7.CrossRefGoogle ScholarPubMed
Menu, E., Garcia, J., Huang, X. et al. A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Research 2008;68:5519–23.CrossRefGoogle ScholarPubMed
Huang, X., Di Liberto, M., Jayabalan, D. et al. Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4. Blood 2012;120(5):1095–106.CrossRefGoogle ScholarPubMed
Manohar, S. M., Rathos, M. J., Sonawane, V., Rao, S. V., Joshi, K. S.Cyclin-dependent kinase inhibitor, P276–00 induces apoptosis in multiple myeloma cells by inhibition of Cdk9-T1 and RNA polymerase II-dependent transcription. Leuk. Res. 2011;35(6):821–30.CrossRefGoogle ScholarPubMed
Rosen, J. M., Jordan, C. T.The increasing complexity of the cancer stem cell paradigm. Science 2009;324:1670–3.CrossRefGoogle ScholarPubMed
Dean, M., Fojo, T., Bates, S.Tumour stem cells and drug resistance. Nat. Rev. Cancer 2005;5:275–84.CrossRefGoogle ScholarPubMed
Brennan, S., Matsui, W.Cancer stem cells: controversies in multiple myeloma. J. Molec. Med. 2009;87:1079–85.CrossRefGoogle ScholarPubMed
Bakkus, M. H., Heirman, C., Van Riet, I., Van Camp, B., Thielemans, K.Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation. Blood 1992;80:2326–35.Google ScholarPubMed
Billadeau, D., Ahmann, G., Greipp, P., Van Ness, B.The bone marrow of multiple myeloma patients contains B cell populations at different stages of differentiation that are clonally related to the malignant plasma cell. J Experimental Med. 1993;178:1023–31.CrossRefGoogle ScholarPubMed
Bergsagel, P. L., Smith, A. M., Szczepek, A. et al. In multiple myeloma, clonotypic B lymphocytes are detectable among CD19+ peripheral blood cells expressing CD38, CD56, and monotypic Ig light chain [published erratum appears in Blood 1995;85(11):436–47].Google ScholarPubMed
Rasmussen, T., Jensen, L., Johnsen, H. E.Levels of circulating CD19+ cells in patients with multiple myeloma. Blood 2000;95:4020.Google ScholarPubMed
Pilarski, L. M., Hipperson, G., Seeberger, K. et al. Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice. Blood 2000;95:1056–65.Google ScholarPubMed
Pilarski, L. M., Belch, A. R.Clonotypic myeloma cells able to xenograft myeloma to nonobese diabetic severe combined immunodeficient mice copurify with CD34+ hematopoietic progenitors. Clinical Cancer Research 2002;8:3198–204.Google ScholarPubMed
Matsui, W., Huff, C. A., Wang, Q. et al. Characterization of clonogenic multiple myeloma cells. Blood 2004;103:2332–6.CrossRefGoogle ScholarPubMed
Hosen, N., Matsuoka, Y., Kishida, S. et al. CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients. Leukemia 2012; e-pub ahead of print 20 April;
Matsui, W., Wang, Q., Barber, J. P. et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Research 2008;68(1):190–7.CrossRefGoogle ScholarPubMed
Kirshner, J., Thulien, K. J., Martin, L. D. et al. A unique three-dimensional model for evaluating the impact of therapy on multiple myeloma. Blood 2008;112:2935–45.CrossRefGoogle ScholarPubMed
Yata, K., Yaccoby, S. The SCID-rat model: a novel in vivo system for primary human myeloma demonstrating growth of CD138-expressing malignant cells. Leukemia 2004;18(11):1891–7.CrossRef
Jakubikova, J., Adamia, S., Kost-Alimova, M. et al. Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. Blood 2011;117:4409–19.CrossRefGoogle ScholarPubMed
Chiron, D., Surget, S., Maga, S. et al. The peripheral CD138+ population but not the CD138− population contains myeloma clonogenic cells in plasma cell leukaemia patients. Br. J. Haematol. 2012;156:679–83.CrossRefGoogle Scholar
Kim, D., Park, C. Y., Medeiros, B. C., Weissman, I. L. CD19-CD45low/-CD38high/CD138+ plasma cells enrich for human tumorigenic myeloma cells. Leukemia 2012; e-pub head of print May 30, 2012.
Kapoor, P., Greipp, P. T., Morice, W. G. et al. Anti-CD20 monoclonal antibody therapy in multiple myeloma. Br. J. Haematol. 2008;141:135–48.CrossRefGoogle ScholarPubMed
Pilarski, L. M., Baigorri, E., Mant, M. J. et al. Multiple myeloma includes phenotypically defined subsets of clonotypic CD20+ B cells that persist during treatment with rituximab. Clinical Medicine Oncology 2008;2:275–87.CrossRefGoogle Scholar
McCarthy, P. L., Owzar, K., Hofmeister, C. C. et al. Lenalidomide after stem-cell transplantation for multiple myeloma. New Engl. J. Med. 2012;366(19):1770–81.CrossRefGoogle ScholarPubMed
Attal, M., Lauwers-Cances, V., Marit, G. et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. New Engl. J. Med. 2012;366(19):1782–91.CrossRefGoogle ScholarPubMed
Peacock, C. D., Wang, Q., Gesell, G. S. et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc. Natl. Acad. Sci. 2007;104:4048–53.CrossRefGoogle ScholarPubMed
Chiron, D., Maga, S., Descamps, G. et al. Critical role of the NOTCH ligand JAG2 in self-renewal of myeloma cells. Blood Cells Molecules Dis. 2012;48:247–53.CrossRefGoogle ScholarPubMed
Matsui, W., Borrello, I., Mitsiades, C.Autologous stem cell transplantation and multiple myeloma cancer stem cells. Biol. Blood Marrow Transplant 2012;18:S27–S32.CrossRefGoogle ScholarPubMed
Spisek, R., Kukreja, A., Chen, L. C. et al. Frequent and specific immunity to the embryonal stem cell-associated antigen SOX2 in patients with monoclonal gammopathy. J. Exp. Med. 2007;204:831–40.CrossRefGoogle ScholarPubMed
He, K., Xu, T., Goldkorn, A.Cancer cells cyclically lose and regain drug-resistant highly tumorigenic features characteristic of a cancer stem-like phenotype. Molecular Cancer Therapeut. 2011;10(6):938–48.CrossRefGoogle ScholarPubMed

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