Haploidization of Human Diploid Metaphase Cells: Is This Genome Reductive Mechanism Opperational in Near-Haploid Leukemia? ()
The present study presents cytogenetics/cytology of haploidization in the origin of a new, fast growing diploid, small cell-type (F-dPCs). The sequence of events was haploid groupings of the chromosomes in normal, human metaphase cells, followed by genomic doubling to homozygousdiploidy. These events were responses to DNA replication stress fromamino acid glutamine deprivation. Importantly, these homozygous cells outgrew normal fibroblasts in 2 - 3 passages—they had gained proliferative advantage (GPA), presumably from loss (LOH) of tumor suppressor genes. They were morphologically changed cells with rounded nuclei that grew in a “streaming” growth pattern and with changed form and size of mitosis, similar to some hyperplasias. The grouping of the chromosomes in metaphase cells was asymmetric with a narrow range around the median (23) (no micro-nuclei), suggesting genetic control. The root-origin of haploidization was evidenced by maternal and paternal genomes occupying separate territories in metaphase cells, which assumedly permitted independent segregations of bichromatid chromosomes. In near-haploid ALL-L1 leukemia the loss of virtually, whole chromosomal complements was judged by SNP array analyses, as a primary event before genomic doubling to hyperdiploidy with LOH. From the present data such specific, non-random loss of chromosomes strongly suggested, a haploidization process capable of genomic doubling, as observed for the “birth” of the small, F-dPCs. This suggestion was supported by this type of leukemia being the L1-type, where L1 signifies small cells. The possibility now exists that a tumorigenic process can be initiated directly from diploid cells through haploid (near-haploid) distributed chromosomes in normal metaphase cells. This event followed by monosomic doublings to UPDs would lead to massive LOH and a return to para-diploidy, a frequent occurrence in many types of tumors. The present simple, cultural derivations of the extraordinary F-dPCs allow GPA-identification and experimental manipulations, perhaps relevant in a vaccine program.
Cite this paper
Conflicts of Interest
The authors declare no conflicts of interest.
|||B. Vogelstein and K. W. Kinzler, “The Multistep Nature of Cancer,” Trends in Genetics, Vol. 9, No. 4, 1993, pp. 138-141. http://dx.doi.org/10.1016/0168-9525(93)90209-Z|
|||I. Bozic, T. Antal, H. Ohtsuki, H. Carter, D. Kim, S. Chen, R. Karchin, et al., “Accumulation of Driver and Passenger Mutations during Tumor Progression,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 43, 2010, pp. 18545-18550. http://dx.doi.org/10.1073/ pnas.1010978107|
|||D. Hanahan and R. A. Weinberg, “Hallmarks of Cancer: The Next Generation,” Cell, Vol. 144, No. 5, 2011, pp. 646-674. http://dx.doi.org/10.1016/j.cell.2011.02.013|
|||S. E. Shackney and T. V. Shanky, “Genetic and Phenotypic Heterogeneity of Human Malignancies: Finding Order in Chaos,” Cytometry, Vol. 21, No. 1, 1995, pp. 2-5. http://dx.doi.org/10.1002/cyto. 990210103|
|||D. J. Gordon, B. Resio and D. Pellman, “Causes and Consequences of Aneuploidy in Cancer,” Nature Reviews. Genetics, Vol. 13, No. 3, 2012, pp. 189-203.|
|||A. A. Sandberg, “Chromosome Abnormalities in Human Cancer and Leukaemia,” Mutation Research, Vol. 247, No. 2, 1991, pp. 231-240. http://dx.doi.org/10.1016/0027-5107(91)90019-K|
|||R. R. Burbano, A. Medeiros, M. I. Medeiros de Amorim, E. M. Lima, A. Mell, J. B. Neto and C. Casartelli, “Cytogenetics of Epiyhelil Hyperplasias of the Human Breast,” Cancer Genetics and Cytogenetics, Vol. 119, No. 1, 2000, pp. 62-66. http://dx.doi.org/10.1016/S0165-4608(99)00175-2|
|||J. Fitzgibbon, L.-L. Smith, M. Raghavan, M. L. Smith, S. Debernardi, S. Skoulakis, D. Lillington, T. A. Lister and B. D. Young, “Association between Uniparental Disomy and Homozygous Gene Mutation in Acute Myeloid Leukemias,” Cancer Research, Vol. 65, 2005, pp. 9252-9154. http://dx.doi.org/10. 1158/0008-5472.CAN-05-2017|
|||L. P. Gondek, R. Tiu, L. O’Keefe, M. A. Sekeres, K. S. Theil and J. P. Maciejewski, “Chromosomal Lesions and Uniparental Disomy Detected by SNP Arrays in MDS, MDS/MPD and MDS-Derived AML,” Blood, Vol. 111, No. 3, 2008, pp. 1534-1542. http://dx.doi.org/10.1182/blood-2007-05-092304|
C. H. Coschi and F. A. Dick, “Chromosome Instability and Deregulated Proliferation: An Unavoidable Duo,” Cellular and Molecular Life Sciences, Vol. 69, No. 12, 2012, pp. 2009-2024.
|||A. J. Holland and D. W. Cleveland, “Losing Balance: The Origin and Impact of Aneuploidy in Cancer,” EMBO, Vol. 13, 2012, pp. 501-514. http://dx.doi.org/10.1038/embor.2012.55|
|||S. J. Pfau and A. Amon, “Chromosomal Instability and Aneuploidy in Cancer: From Yeast to Man,” EMBO, Vol. 13, 2012, pp. 515-527. http://dx.doi.org/10.1038/embor.2012.65|
|||I. Vitale, L. Galluzzi, L. Senovilla, A. Criollo, M. Jemaa, M. Castedo and G. Kroemer, “Illicit Survival of Cancer Cells during Polyploidization and Depolyploidization,” Cell Death and Differentiation, Vol. 18, 2011, pp. 1403-1413. http://dx.doi.org/10.1038/cdd.2010.145|
T. Davoli and T. de Lange, “The Causes and Consequences of Polyploidy in Normal Development and Cancer,” Annual Review of Cell and Developmental Biology, Vol. 27, 2011, pp. 585-610.
|||L. M. Zasadil, E. M. C. Britigan and B. A. Weaver, “2n or Not 2n: Aneuploidy, Polyploidy and Chromosomal Instability in Primary and Tumor Cells,” Seminars in Cell & Developmental Biology, Vol. 24, No. 4, 2013, pp. 370-379. http://dx.doi.org/10.1290/0603019.1|
|||K. H. Walen, “Human Diploid Fibroblast Cells in Senescence: Cycling Through Polyploidy to Mitotic Cells,” In Vitro Cellular & Developmental Biology—Animal, Vol. 42, No. 7, 2006, pp. 216-224. http://dx.doi.org/10.1290/0603019.1|
K. H. Walen, “Bipolar Genome Reductional Division of Human Near-Senescent, Polyploid Fibroblast Cells,” Cancer Genetics and Cytogenetics, Vol. 173, No. 1, 2007, pp. 43-50.
|||K. H. Walen, “Origin of Diplochromosomal Polyploidy in Near-Senescent Fibroblast Cultures: Heterochromatin, Telomeres and Chromosomal Instability (CIN),” Cell Biology International, Vol. 31, No. 12, 2007, pp. 1447-1455. http://dx.doi.org/10.1016/j.cellbi.2007.06.015|
K. H. Walen, “Genetic Stability of Senescence Reverted Cells: Genome Reduction Division of Polyploid Cells, Aneuploidy and Neoplasia,” Cell Cycle, Vol. 7, No. 11, 2008, pp. 1623-1629.
|||H. O. Lee, J. M. Davidson and R. J. Duronio, “Endoreplication: Polyploidy with a Purpose,” Genes & Development, Vol. 23, 2009, pp. 2461-2477. http://dx.doi.org/10.1101/gad.1829209|
|||S. K. Pandit, B. Westendorp and A. de Bruin, “Physiological Significance of Polyploidization in Mammalian Cells,” Trends in Cell Biology, Vol. 23, No. 11, 2013, pp. 556-566.|
|||S. Zhang, I. Mercado-Uribe, B. Sun, J. Kuang and L. Liu, “Generation of Cancer-Stem-Like Cells through the Formation of Polyploid Giant Cancer Cells,” Oncogene, Vol. 33, No. 1, 2014, pp. 116-128.|
|||D. N. Wheatley, “Growing Evidence of the Repopulation of Regressed Tumors by the Division of Giant Cells,” Cell Biology International, Vol. 32, No. 9, 2008, pp. 1029-1030. http://dx.doi.org/10.1016/ j.cellbi.2008.06.001|
|||J. Erenpreisa, K. Salmina, A. Huna, E. A. Kosmacek, M. S. Cragg, F. Ianzini and A. Anisimov, “Polyploid Tumor Cells Elicit Paradiploid Progeny through Depolyploidizing Divisions and Regulated Autophagic Degradation,” Cell Biology International, Vol. 35, No. 7, 2011, pp. 687-695. http://dx.doi.org/10. 1042/CBI20100762|
|||I. B. Raikov, “The Protozoan Nucleus, Morphology and Evolution,” In: M. Alfert, W. Beermann, L. Goldstein, K. R. Porter and P. Sitte, Eds., Cell Biology Monographs, Vol. 9, Springer-Verlag, Wien-New-York, 1982, pp. 209-214.|
|||A. Hunding, “Possible Prepatterns Coverning Mitosis: The Mechnism of Spindle-Free Chromosome Movement in Aulacanthascolymantha,” Journal of Theoretical Biology, Vol. 89, 1981, pp. 353-385.|
K. G. Grell and A. Ruthmann, “Uber die Karyologie des Radiolars Aulachantascolymantha und Feinstruktur Seiner Chromosomen,” Chromosoma, Vol. 15, No. 2, 1964, pp. 185-211.
K. H. Walen, “Genome Reversion Process of Endopolyploidy Confers Chromosome Instability on the Descendent Diploid Cells,” Cell Biology International, Vol. 36, No. 2, 2012, pp. 1-9.
|||K. H. Walen, “Normal Human Cells Acquiring Proliferative Advantage to Hyperplasia-Like Growth-Morphology: Aberrant Progeny Cells Associated with Endopolyploid and Haploid Divisions,” Cancer and Clinical Oncology, Vol. 2, No. 2, 2013, pp. 1-15. http://dx.doi.org/10.5539/cco.v2n2p19|
|||K. H. Walen, “Normal Human Cell Conversion to 3-D Cancer-Like Growth: Genome Damage, Endopolyploidy, Senescence Escape, and Cell Polarity Change/Loss,” Journal of Cancer Therapy, Vol. 2, No. 2, 2011, pp. 181-189. http://dx.doi.org/10.4236/jct.2011.22023|
|||K. H. Walen, “Senescence Arrest of Endopolyploid Cells Renders Senescence into a Mechanism for Positive Tumorigenesis,” In: Tumor Dormancy and Cellular Quiescence and Senescence, Vol. 1: Aging, Cancer, and Noncancer Pathologies, Springer, Berlin, 2013.|
|||J. J. Freed and S. A. Schatz, “Chromosome Aberrations in Cultured Cells Deprived of Single Essential Amino Acid,” Experimental Cell Research, Vol. 55, No. 3, 1969, pp. 393-409. http://dx.doi.org/10. 1016/0014-4827(69)90574-6|
|||R. Phillip, E. Campbell and D. N. Wheatley, “Arginine Aeprivation, Growth Inhibition and Tumor Cell Death: 2. Enzymatic Degradation of Arginine in Normal and Malignant Cell Cultures,” British Journal of Cancer, Vol. 88, No. 4, 2003, pp. 613-623. http://dx.doi.org/10.1038/sj.bjc.6600681|
|||R. J. Deberardinis and T. Cheng, “Q’s Next: The Diverse Functions of Glutamine in Metabolism, Cell Biology and Cancer,” Oncogene, Vol. 29, No. 3, 2010, pp. 313-324. http://dx.doi.org/10.1038/ onc.2009.358|
|||J. R. Cantor and D. M. Sabatini, “Cancer Cell Metabolism: One Hallmark, Many Faces,” Cancer Discovery, Vol. 2, No. 10, 2012, pp. 899-905.|
|||C. L. Huskins, “Segregation and Reduction in Somatic Tissues. I. Initial Observations on Allium cepa,” Journal of Heredity, Vol. 39, 1948, pp. 310-325.|
|||E. Glass, “Das Problem der Gesonderung in den Mitosen Unbehandelter Rattenlebern,” Chromosoma, Vol. 8, No. 1, 1957, pp. 468-492. http://dx.doi.org/10.1007/BF01259515|
|||T. T. Glazko, “Chromosomes Subdividing to Haploid Sets in Diploid Metaphase Plates of Some Mammalian Species,” Proceedings of the 15th International Chromosome Conference, Brunel University, 5-10 September 2004, p. 63.|
|||W. Mayer, A. Smith, R. Fundele and T. Haaf, “Spatial Separation of Parental Genomes in Preimplantation Mouse Embryos,” Journal of Cell Biology, Vol. 148, No. 4, 2000, pp. 629-634. http://dx.doi.org/10.1083/jcb.148.4.629|
J. Travis, “Return of the Matrix,” Science, Vol. 318, No. 5855, 2007, pp. 1400-1401.
|||J. Picket-Heaps and A. Forer, “Mitosis: Spindle Evolution and Matrix Model,” Protoplasma, Vol. 235, No. 1-4, 2009, pp. 91-99. http://dx.doi.org/10.1007/s00709-009-0030-2|
|||M. V. Blagosklonny, “Cell Immortality and Hallmarks of Cancer,” Cell Cycle, Vol. 2, No. 4, 2003, pp. 296-299. http://dx.doi.org/10.4161/cc.2.4.470|
K. L. Chan, T. Palmai-Pallal, S. Ying and I. D. Hickson, “Replication Stress Induces Sister Chromatid Bridging at Fragile Site in Mitosis,” Nature Cell Biology, Vol. 11, No. 6, 2009, pp. 753-760.
|||K. H. Walen, “Spontaneous Cell Transformation: Karyoplasts Derived from Multinucleated Cells Produce New Cell Growth in Senescent Human Epithelial Cell Cultures,” In Vitro Cellular & Developmental Biology, Vol. 40, No. 5-6, 2004, pp. 150-158. http://dx.doi.org/10.1290/1543-706X (2004)40<150:SCTKDF>2.0.CO;2|
G. E. Sarto, P. A. Stubblefield, J. Lurain and E. Therman, “Mechanisms of Growth in Hydatidiform Moles,” American Journal of Obstetrics & Gynecology, Vol. 148, No. 7, 1984, pp. 1014-1023.
|||Y. Kukita, K. Miyatake, R. Stokowski, D. Hinds, K. Higasa, N. Wake, et al., “Genome-wide Definitive Haplotypes Determined Using a Collection of Complete Hydatidiform Moles,” Genome Research, Vol. 15, No. 11, 2013, pp. 1511-1518. http://dx.doi.org/10.1101/gr.4371105|
|||F. Mitelman, “Catalog of Chromosome Aberrations in Cancer,” Alan Liss, Inc., New York, 1988.|
S. Safavi, E. Forestier, I. Golovleva, G. Barbany, K. H. Nord, A. V. Moorman, C. J. Harrison, B. Johansson and K. Paulsson, “Loss of Chromosomes Is the Primary Event in Near-Haploid and Low-Hypodiploid Acute Lymphoblastic Leukaemia,” Leukemia, Vol. 27, No. 1, 2013, pp. 248-250.
|||S. Heim and F. Mitelman, “Cancer Cytogenetics: Chromosomal and Molecular Genetic Aberrations of Tumor Cells,” 2nd Edition, Wiley-Liss, Inc., New York, 1995.|
|||L. Olsson, K. Paulsson, J. V. Bovee and K. H. Nord, “Clonal Evolution Through Loss of Chromosomes and Subsequent Polyploidization in Chondrosarcoma,” PLoS ONE, Vol. 6, No. 9, 2011, Article ID: e24977.|
|||N. Mandahl, B. Johansson, F. Mertens and F. Mitelman, “Disease-Associated Patterns of Disomic Chromosomes in Hyperhaploid Neoplasms,” Genes, Chromosomes and Cancer, Vol. 51, No. 6, 2012, pp. 536-544. http://dx.doi.org/10.1002/gcc.21947|
|||Z. Storchova and D. Pellman, “From Polyploidy to Aneuploidy, Genome Instability and Cancer,” Nature Reviews Molecular Cell Biology, Vol. 5, 2004, pp. 45-54. http://dx.doi.org/10.1038/nrm1276|
|||A. Levan and T. S. Hauschka, “Endomitotic Reduplication Mechanisms in Ascites Tumors,” Journal of the National Cancer Institute, Vol. 14, No. 1, 1953, pp. 1-43.|
|||T. Davoli, E. L. Denchi and T. de Lange, “Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy,” Cell, Vol. 141, No. 1, 2010, pp. 81-93. http://dx.doi.org/10.1016/j.cell.2010.01.031|
|||T. Boveri, “ZurFrage der Entstehung Maligner Tumoren,” Fischer, Jena, 1914.|
|||L. P. Bignold, B. L. D. Coghlan and H. P. A. Jersmann, “David von Hansemann: Contributions to Oncology: Context, Comments and Translations,” Birkhauser Verlag, Basel, 2007.|
|||R. G. Nagele, M. R. Jones, H. G. Nguyen, D. J. McCrann, C. St. Hilaire, B. Schreiber, et al., “Precise Spatial Positioning of Chromosomes During Prometaphase: Evidence for Chromosomal Order,” Science, Vol. 270, No. 5243, 1995, pp. 1831-1835.|
|||A. Bolzer, G. Kreth, I. Solovei, D. Koehler, K. Saracoglu, C. Fauth, et al., “Three-Dimensional Maps of all Chromosomes in Human Male Fibroblast Nuclei and Prometaphase Rosettes,” PLoS Biology, Vol. 3, No. 5, 2005, pp. 826-842.|
|||S. F. Patten, “Diagnostic Cytopathology of the Uterine Cervix,” Monographs in Clinical Cytology, Vol. 3, S. Karger, Basel, 1978, pp. 20-25.|
|||M. H. Stoler, “Does Every Little Cell Count? Don’t ASCUS,” Cancer Cytopathology, Vol. 87, No. 2, 1999, pp. 45-47.|
|||A. S. Wilkins and R. Holliday, “The Evolution of Meiosis from Mitosis,” Genetics, Vol. 181, No. 1, 2009, pp. 3-12. http://dx.doi.org/10.1534/genetics.108.099762|
|||L. M. Shabad, “Precancerous Morphological Lesions,” Journal of the National Cancer Institute, Vol. 50, 1973, pp. 1421-1428.|
|||P. P. Rosen, “Proliferative Breast ‘Disease’: An Unresolved Diagnostic Dilemma,” Cancer, Vol. 71, No. 12, 1993, pp. 3798-3807. http://dx.doi.org/10.1002/1097-0142(19930615)71:12<3798::AID-CNCR2820711203>3.0.CO;2-S|
|||G. Belge, L. Roque, J. Soares, S. Bruckmann, B. Thode, E. Fonseca, A. Clode, S. Bartnitzke, S. Castedo and J. Bullerdiek, “Cytogenetic Investigations of 340 Thyroid Hyperplasias and Adenoma Revealing Correlations Between Cytogenetic Findings and Histology,” Cancer Genetics and Cytogenetics, Vol. 101, No. 1, 1998, pp. 42-48. http://dx.doi.org/10.1016/S0165-4608(97)00057-5|
|||C. Royer and X. Lu, “Epithelial Cell Polarity: A Major Gatekeeper against Cancer?” Cell Death and Differentiation, Vol. 18, No. 9, 2011, pp. 1470-1477. http://dx.doi.org/10.1038/cdd.2011.60|
|||W. S. Saunders, M. Shuster, X. Huang, B. Gharaibe, A. H. Enyenihi, I. Petersen and S. M. Gollin, “Chromosomal Instability and Cytoskeletal Defects in Oral Cancer Cells,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 1, 2000, pp. 303-308.|
|||R. G. Steinbeck, “Dysplasia in View of the Cell Cycle,” European Journal of Histochemistry, Vol. 48, No. 3, 2004, pp. 203-211.|
|||E. White and R. S. DiPaola, “The Double-Edge Sword of Autophagy Modulation in Cancer,” Clinical Cancer Research, Vol. 15, No. 17, 2009, pp. 5308-5316.|
|||E. Morselli, L. Galluzzi, O. Kepp, J. M. Vicencio, A. Criollo, M. C. Maiuri and G. Kroemer, “Antiand Pro-Tumor Functions of Autophagy,” Biochimica et Biophysica Acta, Vol. 1793, No. 9, 2009, pp. 1524-1532.|
|||J. H. Back and A. L. Kim, “The Expanding Relevance of Nuclear mTOR in Carcinogenesis,” Cell Cycle, Vol. 10, No. 22, 2011, pp. 3849-3852. http://dx.doi.org/10.4161/cc.10.22.18329|
Copyright © 2020 by authors and Scientific Research Publishing Inc.
This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.