Epigenetics wins over genetics: induction of differentiation in tumor cells.

Malignant cells are genetically abnormal, but can the malignant phenotype revert to a non-malignant phenotype without correcting these genetic abnormalities? It has been found that this reversion can be achieved by reprogramming tumor cells by epigenetic changes induced by differentiation. The epigenetic suppression of malignancy by inducing differentiation bypasses the genetic abnormalities in tumor cells. Studies with myeloid leukemic cells have shown that some leukemic cells can be induced to differentiate by cytokines that control normal hematopoiesis, and that myeloid leukemic cells resistant to normal cytokines can be induced to differentiate by compounds that use alternative differentiation pathways. The epigenetic reprogramming of tumor cells by inducing differentiation has also been found with other types of tumors and can be used for tumor therapy. By this reversion of the malignant to non-malignant phenotype, epigenetics wins over genetics.

[1]  Y. Saunthararajah,et al.  Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. , 1999, Cancer research.

[2]  Falk Weih,et al.  Analysis of CpG methylation and genomic footprinting at the tyrosine aminotransferase gene: DNA methylation alone is not sufficient to prevent protein binding in vivo. , 1991, The EMBO journal.

[3]  J. Lotem,et al.  The Network of Hematopoietic Cytokines , 1994, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[4]  M. Azim Surani,et al.  Reprogramming of genome function through epigenetic inheritance , 2001, Nature.

[5]  L. Sachs,et al.  Developmental potential of myeloid leukemia cells injected into midgestation embryos. , 1984, Developmental biology.

[6]  J. A. McBain,et al.  Bryostatin 1 antagonizes the terminal differentiating action of 12-O-tetradecanoylphorbol-13-acetate in a human colon cancer cell. , 1988, Carcinogenesis.

[7]  G. Klein,et al.  Suppression of Malignancy by Cell Fusion , 1969, Nature.

[8]  P. Marks,et al.  Histone deacetylases and cancer: causes and therapies , 2001, Nature Reviews Cancer.

[9]  J. Lotem,et al.  Control of in vivo differentiation of myeloid leukemic cells. , 1988, Leukemia.

[10]  L. Sachs.  The adventures of a biologist: prenatal diagnosis, hematopoiesis, leukemia, carcinogenesis, and tumor suppression. , 1995, Advances in cancer research.

[11]  滝沢 琢己.  DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain , 2002 .

[12]  S. Warren,et al.  TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. , 2000, Cancer research.

[13]  V. Lallemand-Breitenbach,et al.  Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission , 2001, Oncogene.

[14]  J. Lotem,et al.  Different blocks in the differentiation of myeloid leukemic cells. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[15]  L. Sachs,et al.  Control of normal differentiation of myeloid leukemic cells to macrophages and granulocytes. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[16]  L. Sachs,et al.  The induction of clones of normal mast cells by a substance from conditioned medium. , 1966, Experimental cell research.

[17]  B. Cairns.  Emerging roles for chromatin remodeling in cancer biology. , 2001, Trends in cell biology.

[18]  E. Flemington,et al.  CpG methylation as a mechanism for the regulation of E2F activity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[19]  L. Sachs,et al.  Characterization of the inducer required for the development of macrophage and granulocyte colonies. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[20]  W. Sadee,et al.  Neuronal cell differentiation of human neuroblastoma cells by retinoic acid plus herbimycin A. , 1988, Cancer research.

[21]  B. Deroo,et al.  Glucocorticoid receptor-mediated chromatin remodeling in vivo , 2001, Oncogene.

[22]  L. Sachs,et al.  FORMATION OF PURE SUSPENSIONS OF MAST CELLS IN TISSUE CULTURE BY DIFFERENTIATION OF LYMPHOID CELLS FROM THE MOUSE THYMUS. , 1963, Journal of the National Cancer Institute.

[23]  C. Chomienne,et al.  Effect of 5-aza-2′-deoxycytidine and vitamin D3 analogs on growth and differentiation of human myeloid leukemic cells , 1998, Cancer Chemotherapy and Pharmacology.

[24]  G. Klein.  The role of gene dosage and genetic transpositions in carcinogenesis , 1981, Nature.

[25]  A. Leutz,et al.  Chromatin remodeling in development and differentiation. , 2001, Current opinion in genetics & development.

[26]  A. Bird,et al.  Methylation-Induced Repression— Belts, Braces, and Chromatin , 1999, Cell.

[27]  M. Privalsky,et al.  Arsenic Trioxide Is a Potent Inhibitor of the Interaction of SMRT Corepressor with Its Transcription Factor Partners, Including the PML-Retinoic Acid Receptor α Oncoprotein Found in Human Acute Promyelocytic Leukemia , 2001, Molecular and Cellular Biology.

[28]  L. Sachs,et al.  The control of hematopoiesis and leukemia: from basic biology to the clinic. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[29]  I. Olsson,et al.  Myeloid cell differentiation: the differentiation inducing factors of myeloid leukemia cells. , 1988, Leukemia.

[30]  K. Kaushansky.  Thrombopoietin the primary regulator of platelet production. , 1995, Trends in endocrinology and metabolism: TEM.

[31]  J. Lotem,et al.  Mechanisms that uncouple growth and differentiation in myeloid leukemia cells: restoration of requirement for normal growth-inducing protein without restoring induction of differentiation-inducing protein. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[32]  L. Sachs,et al.  Feedback inhibition of the development of macrophage and granulocyte colonies. I. Inhibition by macrophage. , 1967, Proceedings of the National Academy of Sciences of the United States of America.

[33]  L. Sachs.  The control of growth and differentiation in normal and leukemic blood cells , 1990, Cancer.

[34]  Xin Wang,et al.  Purified hematopoietic stem cells can differentiate into hepatocytes in vivo , 2000, Nature Medicine.

[35]  L. Larsson,et al.  Interferon‐γ cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition of human neuroblastoma cells , 2001, International journal of cancer.

[36]  L. Kanz,et al.  Developmental regulation of myeloid gene expression and demethylation during ex vivo culture of peripheral blood progenitor cells. , 1996, Blood.

[37]  J. Lotem,et al.  In vivo induction of normal differentiation in myeloid leukemia cells. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[38]  L. Sachs,et al.  Participation of myeloid leukaemic cells injected into embryos in haematopoietic differentiation in adult mice , 1982, Nature.

[39]  J. Rowley,et al.  The critical role of chromosome translocations in human leukemias. , 1998, Annual review of genetics.

[40]  N. Rosen,et al.  The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. , 2001, Cancer research.

[41]  S. Parsons,et al.  Interleukin-6- and Cyclic AMP-Mediated Signaling Potentiates Neuroendocrine Differentiation of LNCaP Prostate Tumor Cells , 2001, Molecular and Cellular Biology.

[42]  C. Bloomfield,et al.  All-trans-Retinoic Acid in Acute Promyelocytic Leukemia , 2000 .

[43]  J. Lotem,et al.  The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin-6. , 1988, Blood.

[44]  G Cossu,et al.  Muscle regeneration by bone marrow-derived myogenic progenitors. , 1998, Science.

[45]  L. Sachs,et al.  The cloning of normal "mast" cells in tissue culture. , 1965, Journal of cellular physiology.

[46]  P. Fisher,et al.  Differentiation therapy of human cancer: basic science and clinical applications. , 2001, Pharmacology & therapeutics.

[47]  L. Sachs.  The Wellcome Foundation Lecture, 1986 - The molecular regulators of normal and leukaemic blood cells , 1987, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[48]  Lucia Altucci,et al.  The promise of retinoids to fight against cancer , 2001, Nature Reviews Cancer.

[49]  A. Rao,et al.  T cell differentiation: a mechanistic view. , 2000, Current opinion in immunology.

[50]  L. Sachs,et al.  Reversion of Properties in Cells transformed by Polyoma Virus , 1968, Nature.

[51]  T. Farrah,et al.  Molecular cloning of a ligand for the flt3 flk-2 tyrosine kinase receptor: A proliferative factor for primitive hematopoietic cells , 1993, Cell.

[52]  Z. Paroush,et al.  Dynamics of demethylation and activation of the α-actin gene in myoblasts , 1990, Cell.

[53]  A. Wolffe,et al.  Chromatin remodeling: why it is important in cancer , 2001, Oncogene.

[54]  Andrew J. Bannister,et al.  Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain , 2001, Nature.

[55]  T. Hashimshony,et al.  DNA methylation models histone acetylation , 1998, Nature.

[56]  H. Saito,et al.  Histone acetylation induced by granulocyte colony-stimulating factor in a map kinase-dependent manner. , 2001, Biochemical and biophysical research communications.

[57]  J. Herman,et al.  DNA methylation, chromatin inheritance, and cancer , 2001, Oncogene.

[58]  J. Lotem,et al.  Indirect induction of differentiation of normal and leukemic myeloid cells by recombinant interleukin 1. , 1989, Leukemia research.

[59]  J. Lotem,et al.  Selective regulation of the activity of different hematopoietic regulatory proteins by transforming growth factor beta 1 in normal and leukemic myeloid cells. , 1990, Blood.

[60]  H. Yamana,et al.  Induction of terminal differentiation and apoptosis in human colonic carcinoma cells by brefeldin A, a drug affecting ganglioside biosynthesis , 1999, FEBS letters.

[61]  P. Pandolfi,et al.  Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. , 2001, The Journal of clinical investigation.

[62]  O. Witte.  Steel locus defines new multipotent growth factor , 1990, Cell.

[63]  D. Goeddel,et al.  Genomic cloning and heterologous expression of human differentiation-stimulating factor. , 1989, DNA.

[64]  G. Benvenuto,et al.  Cell-specific transcriptional regulation and reactivation of galectin-1 gene expression are controlled by DNA methylation of the promoter region , 1996, Molecular and cellular biology.

[65]  A. Kelso,et al.  Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). , 1987, The EMBO journal.

[66]  P. Marks,et al.  Erythroleukemic differentiation. , 1978, Annual review of biochemistry.

[67]  J. Lotem,et al.  In vivo control of differentiation of myeloid leukemic cells by recombinant granulocyte-macrophage colony-stimulating factor and interleukin 3. , 1988, Blood.

[68]  L. Sachs.  Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukaemia , 1978, Nature.

[69]  C. Bloomfield,et al.  All-trans-retinoic acid in acute promyelocytic leukemia. , 1997, The New England journal of medicine.

[70]  M. Szyf,et al.  Interleukin-6 Regulation of the Human DNA Methyltransferase (HDNMT) Gene in Human Erythroleukemia Cells* , 2001, The Journal of Biological Chemistry.

[71]  L. Kedes,et al.  Acetylation of MyoD directed by PCAF is necessary for the execution of the muscle program. , 1999, Molecular cell.

[72]  M. Szyf,et al.  Demethylase Activity Is Directed by Histone Acetylation* , 2001, The Journal of Biological Chemistry.

[73]  J. Herman,et al.  Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer , 1999, Nature Genetics.

[74]  H. Huang,et al.  Carboxypeptidase A3 (CPA3): a novel gene highly induced by histone deacetylase inhibitors during differentiation of prostate epithelial cancer cells. , 1999, Cancer research.

[75]  J. Lotem,et al.  Cytokine control of developmental programs in normal hematopoiesis and leukemia , 2002, Oncogene.

[76]  Neil D. Theise,et al.  Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell , 2001, Cell.

[77]  L. Sachs,et al.  Normal differentiation of myeloid leukaemic cells induced by a differentiation-inducing protein. , 1972, Nature: New biology.

[78]  J. Ihle,et al.  Procedures for the purification of interleukin 3 to homogeneity. , 1982, Journal of immunology.

[79]  J. Lotem,et al.  In vivo inhibition of the development of myeloid leukemia by injection of macrophage‐and granulocyte‐inducing protein , 1981, International journal of cancer.

[80]  L. Sachs.  Cell differentiation and bypassing of genetic defects in the suppression of malignancy. , 1987, Cancer research.

[81]  L. Sachs,et al.  Constitutive gene expression in myeloid leukemia and cell competence for induction of differentiation by the steroid dexamethasone. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[82]  Guoqiang Chen,et al.  Arsenic trioxide, a therapeutic agent for APL , 2001, Oncogene.

[83]  S. Minucci,et al.  Methyltransferase Recruitment and DNA Hypermethylation of Target Promoters by an Oncogenic Transcription Factor , 2002, Science.

[84]  J. Spivak,et al.  Commentary on and reprint of Pluznik DH, Sachs L, The cloning of normal “mast” cells in tissue culture, in Journal of Cellular and Comparative Physiology (1965) 66:319–324 , 2000 .

[85]  W. Reik,et al.  Epigenetic Reprogramming in Mammalian Development , 2001, Science.

[86]  J. Lotem,et al.  Control of in vivo differentiation of myeloid leukemic cells. iv. inhibition of leukemia development by myeloid differentiation‐inducing protein , 1984, International journal of cancer.

[87]  Karl Mechtler,et al.  Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins , 2001, Nature.

[88]  T. Kishimoto,et al.  Gp130 and the interleukin-6 family of cytokines. , 1997, Annual review of immunology.

[89]  S. Brandt,et al.  P/CAF‐mediated acetylation regulates the function of the basic helix–loop–helix transcription factor TAL1/SCL , 2000, The EMBO journal.

[90]  L. Sachs,et al.  In vitro control of the development of macrophage and granulocyte colonies. , 1966, Proceedings of the National Academy of Sciences of the United States of America.

[91]  Z. Paroush,et al.  Dynamics of demethylation and activation of the alpha-actin gene in myoblasts. , 1990, Cell.

[92]  D. Metcalf.  Granulocyte-macrophage colony-stimulating factors , 1985, Cell.

[93]  É. Mezey,et al.  Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[94]  Keith D Robertson,et al.  DNA methylation, methyltransferases, and cancer , 2001, Oncogene.

[95]  L. Sachs.  The molecular control of blood cell development. , 1987, Science.

[96]  B. Vogelstein,et al.  Differentiation of leukemia cells to polymorphonuclear leukocytes in patients with acute nonlymphocytic leukemia. , 1986, The New England journal of medicine.

[97]  E. Selker,et al.  A histone H3 methyltransferase controls DNA methylation in Neurospora crassa , 2001, Nature.