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5. Identification of Flt(super 3+) lympho-myeloid stem cells lacking erythro-megakaryocytic potential: A revised road map for adult blood lineage commitment

Author

Adolfsson, Jorgen, Mansson, Robert, Buza-Vidas, Natalija, Hultquist, Anne, Liuba, Karina, Jensen, Christina T., Bryder, David, Lipang Yang, Borge, Ole-Johan, Thoren, Lina A.M., Anderson, Kristina, Sitnicka, Ewa, Sasaki, Yutaka, Sigvardsson, Mikael, and Jacobsen, Sten Erik W.

Subjects
Bone marrow cells -- Analysis, Stem cells -- Analysis, Cell research, Biological sciences
Abstract

A study conducted presents an evidence for a population of cells, which although sustaining a high proliferative and combined lympho-myeloid differentiation potential, have lost the ability to adopt erythroid and megakaryocyte lineage fates. It is shown that cells in the Lin(super -1)Sca-1(super +1)-kit(super +1) hematopoietic stem cell (HSC) compartment coexpressing high levels of the tyrosine kinase receptor Flt3 sustains granulocyte, monocyte, and B and T cell potentials.

Published
2005

8. PHF6 and DNMT3A mutations are enriched in distinct subgroups of mixed phenotype acute leukemia with T-lineage differentiation

Author

Xiao, Wenbin, primary, Bharadwaj, Maheetha, primary, Levine, Max, primary, Farnoud, Noushin, primary, Pastore, Friederike, primary, Getta, Bartlomiej M., primary, Hultquist, Anne, primary, Famulare, Christopher, primary, Medina, Juan S., primary, Patel, Minal A., primary, Gao, Qi, primary, Lewis, Natasha, primary, Pichardo, Janine, primary, Baik, Jeeyeon, primary, Shaffer, Brian, primary, Giralt, Sergio, primary, Rampal, Raajit, primary, Devlin, Sean, primary, Cimera, Robert, primary, Zhang, Yanming, primary, E. Arcila, Maria, primary, Papaemmanuil, Elli, primary, Levine, Ross L., primary, and Roshal, Mikhail, primary

Published
2018
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10. De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia

Author

Hyrenius-Wittsten, Axel, primary, Pilheden, Mattias, additional, Sturesson, Helena, additional, Hansson, Jenny, additional, Walsh, Michael P., additional, Song, Guangchun, additional, Kazi, Julhash U., additional, Liu, Jian, additional, Ramakrishan, Ramprasad, additional, Garcia-Ruiz, Cristian, additional, Nance, Stephanie, additional, Gupta, Pankaj, additional, Zhang, Jinghui, additional, Rönnstrand, Lars, additional, Hultquist, Anne, additional, Downing, James R., additional, Lindkvist-Petersson, Karin, additional, Paulsson, Kajsa, additional, Järås, Marcus, additional, Gruber, Tanja A., additional, Ma, Jing, additional, and Hagström-Andersson, Anna K., additional

Published
2018
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11. Pharmacologically relevant doses of valproate upregulate CD20 expression in three diffuse large B-cell lymphoma patients in vivo.

Author

Kofoed Damm, Jesper, Gordon, Sandra, Ehinger, Mats, Jerkeman, Mats, Gullberg, Urban, Hultquist, Anne, Drott, Kristina, Kofoed Damm, Jesper, Gordon, Sandra, Ehinger, Mats, Jerkeman, Mats, Gullberg, Urban, Hultquist, Anne, and Drott, Kristina

Abstract

Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have been proposed as potential new therapies for lymphoid malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma for which standard first line treatment is the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). The HDACi valproate, which has for long been utilized in anti-convulsive therapy, has been shown to sensitize to chemotherapy in vitro. Valproate upregulates expression of CD20 in lymphoma cell lines; therefore, 48 hour pre-treatment with valproate before first line R-CHOP in DLBCL stages II-IV is evaluated in the phase I clinical trial VALFRID; Valproate as First line therapy in combination with Rituximab and CHOP in Diffuse large B-cell lymphoma.

Published
2015

13. PHF6and DNMT3Amutations are enriched in distinct subgroups of mixed phenotype acute leukemia with T-lineage differentiation

Author

Xiao, Wenbin, Bharadwaj, Maheetha, Levine, Max, Farnhoud, Noushin, Pastore, Friederike, Getta, Bartlomiej M., Hultquist, Anne, Famulare, Christopher, Medina, Juan S., Patel, Minal A., Gao, Qi, Lewis, Natasha, Pichardo, Janine, Baik, Jeeyeon, Shaffer, Brian, Giralt, Sergio, Rampal, Raajit, Devlin, Sean, Cimera, Robert, Zhang, Yanming, E. Arcila, Maria, Papaemmanuil, Elli, Levine, Ross L., and Roshal, Mikhail

Abstract

The genetic aberrations that drive mixed phenotype acute leukemia (MPAL) remain largely unknown, with the exception of a small subset of MPALs harboring BCR-ABL1and MLLtranslocations. We performed clinicopathologic and genetic evaluation of 52 presumptive MPAL cases at Memorial Sloan Kettering Cancer Center. Only 29 out of 52 (56%) cases were confirmed to be bona fide MPAL according to the 2016 World Heath Organization classification. We identified PHF6and DNMT3Amutations as the most common recurrent mutations in MPAL, each occurring in 6 out of 26 (23%) cases. These mutations are mutually exclusive of each other and BCR-ABL1/MLLtranslocations. PHF6- and DNMT3A-mutated MPAL showed marked predilection for T-lineage differentiation (5/6 PHF6mutated, 6/6 DNMT3Amutated). PHF6-mutated MPAL occurred in a younger patient cohort compared with DNMT3A-mutated cases (median age, 27 years vs 61 years, P< .01). All 3 MPAL cases with both T- and B-lineage differentiation harbored PHF6mutations. MPAL with T-lineage differentiation was associated with nodal or extramedullary involvement (9/15 [60%] vs 0, P= .001) and a higher relapse incidence (78% vs 22%, P= .017) compared with those without T-lineage differentiation. Sequencing studies on flow-cytometry–sorted populations demonstrated that PHF6mutations are present in all blast compartments regardless of lineage differentiation with high variant allele frequency, implicating PHF6as an early mutation in MPAL pathogenesis. In conclusion, PHF6and DNMT3Amutations are the most common somatic alterations identified in MPAL and appear to define 2 distinct subgroups of MPAL with T-lineage differentiation with inferior outcomes.

Published
2018
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16. Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells

Author

Böiers, C, Carrelha, J, Lutteropp, M, Luc, S, Green, J, Azzoni, E, Woll, P, Mead, A, Hultquist, A, Swiers, G, Perdiguero, E, Macaulay, I, Melchiori, L, Luis, T, Kharazi, S, Bouriez-Jones, T, Deng, Q, Pontén, A, Atkinson, D, Jensen, C, Sitnicka, E, Geissmann, F, Godin, I, Sandberg, R, de Bruijn, M, Jacobsen, S, Böiers, Charlotta, Carrelha, Joana, Lutteropp, Michael, Luc, Sidinh, Green, Joanna C A, Azzoni, Emanuele, Woll, Petter S, Mead, Adam J, Hultquist, Anne, Swiers, Gemma, Perdiguero, Elisa Gomez, Macaulay, Iain C, Melchiori, Luca, Luis, Tiago C, Kharazi, Shabnam, Bouriez-Jones, Tiphaine, Deng, Qiaolin, Pontén, Annica, Atkinson, Deborah, Jensen, Christina T, Sitnicka, Ewa, Geissmann, Frederic, Godin, Isabelle, Sandberg, Rickard, de Bruijn, Marella F T R, Jacobsen, Sten Eirik W, Böiers, C, Carrelha, J, Lutteropp, M, Luc, S, Green, J, Azzoni, E, Woll, P, Mead, A, Hultquist, A, Swiers, G, Perdiguero, E, Macaulay, I, Melchiori, L, Luis, T, Kharazi, S, Bouriez-Jones, T, Deng, Q, Pontén, A, Atkinson, D, Jensen, C, Sitnicka, E, Geissmann, F, Godin, I, Sandberg, R, de Bruijn, M, Jacobsen, S, Böiers, Charlotta, Carrelha, Joana, Lutteropp, Michael, Luc, Sidinh, Green, Joanna C A, Azzoni, Emanuele, Woll, Petter S, Mead, Adam J, Hultquist, Anne, Swiers, Gemma, Perdiguero, Elisa Gomez, Macaulay, Iain C, Melchiori, Luca, Luis, Tiago C, Kharazi, Shabnam, Bouriez-Jones, Tiphaine, Deng, Qiaolin, Pontén, Annica, Atkinson, Deborah, Jensen, Christina T, Sitnicka, Ewa, Geissmann, Frederic, Godin, Isabelle, Sandberg, Rickard, de Bruijn, Marella F T R, and Jacobsen, Sten Eirik W

Abstract

In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the innate immune system are formed early in development, whereas lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we demonstrate that the embryonic lymphoid commitment process initiates earlier than previously appreciated, prior to emergence of definitive HSCs, through establishment of a previously unrecognized entirely immune-restricted and lymphoid-primed progenitor. Notably, this immune-restricted progenitor appears to first emerge in the yolk sac and contributes physiologically to the establishment of lymphoid and some myeloid components of the immune-system, establishing the lymphomyeloid lineage restriction process as an early and physiologically important lineage-commitment step in mammalian hematopoiesis

Published
2013

17. Lymphomyeloid Contribution of an Immune-Restricted Progenitor Emerging Prior to Definitive Hematopoietic Stem Cells

Author

Böiers, Charlotta, primary, Carrelha, Joana, additional, Lutteropp, Michael, additional, Luc, Sidinh, additional, Green, Joanna C.A., additional, Azzoni, Emanuele, additional, Woll, Petter S., additional, Mead, Adam J., additional, Hultquist, Anne, additional, Swiers, Gemma, additional, Perdiguero, Elisa Gomez, additional, Macaulay, Iain C., additional, Melchiori, Luca, additional, Luis, Tiago C., additional, Kharazi, Shabnam, additional, Bouriez-Jones, Tiphaine, additional, Deng, Qiaolin, additional, Pontén, Annica, additional, Atkinson, Deborah, additional, Jensen, Christina T., additional, Sitnicka, Ewa, additional, Geissmann, Frederic, additional, Godin, Isabelle, additional, Sandberg, Rickard, additional, de Bruijn, Marella F.T.R., additional, and Jacobsen, Sten Eirik W., additional

Published
2013
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18. TGF-beta enforces senescence in Myc-transformed hematopoietic tumor cells through induction of Mad1 and repression of Myc activity

Author

Wu, Siqin, Hultquist, Anne, Hydbring, Per, Cetinkaya, Cihan, Öberg, Fredrik, Larsson, Lars-Gunnar, Wu, Siqin, Hultquist, Anne, Hydbring, Per, Cetinkaya, Cihan, Öberg, Fredrik, and Larsson, Lars-Gunnar

Abstract

Inhibition of tumor growth factor (TGF)-beta-mediated cell cycle exit is considered an important tumorigenic function of Myc oncoproteins. Here we found that TGF-beta1 enforced G(1) cell cycle arrest and cellular senescence in human U-937 myeloid tumor cells ectopically expressing v-Myc, which contains a stabilizing mutation frequently found in lymphomas. This correlated with induced expression of the Myc antagonist Mad1, resulting in replacement of Myc for Mad1 at target promoters, reduced histone acetylation and strong repression of Myc-driven transcription. The latter was partially reversed by histone deacetylase (HDAC) inhibitors, consistent with involvement of Mad1. Importantly, knockdown of MAD1 expression prevented TGF-beta1-induced senescence, underscoring that Mad1 is a crucial component of this process. Enforced Mad1 expression sensitized U-937-myc cells to TGF-beta and restored phorbol ester-induced cell cycle exit, but could not alone induce G(1) arrest, suggesting that Mad1 is required but not sufficient for cellular senescence. Our results thus demonstrate that TGF-beta can override Myc activity despite a stabilizing cancer mutation and induce senescence in myeloid tumor cells, at least in part by induction of Mad1. TGF-beta-induced senescence, or signals mimicking this pathway, could therefore potentially be explored as a therapeutic principle for treating hematopoietic and other tumors with deregulated MYC expression.

Published
2009
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19. Establishment of lympho-myeloid restricted progenitors prior to the emergence of definitive hematopoietic stem cells

Author

Böiers, Charlotta, primary, Lutteropp, Michael, additional, Luc, Sidinh, additional, Woll, Petter, additional, Mead, Adam, additional, Hultquist, Anne, additional, Carrelha, Joana, additional, Macaulay, Iain, additional, Swiers, Gemma, additional, Melchiori, Luca, additional, Luis, Tiago, additional, Kharazi, Shabnam, additional, Bouriez-Jones, Tiphaine, additional, Deng, Qiaolin, additional, Pontén, Annica, additional, Jensen, Christina, additional, Sitnicka, Ewa, additional, Sandberg, Rickard, additional, de Bruijn, Marella, additional, and Jacobsen, Sten Eirik, additional

Published
2013
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20. Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells

Author

Cetinkaya, Cihan, Hultquist, Anne, Su, Yingtao, Wu, Siqin, Bahram, Fuad, Påhlman, Sven, Guzhova, Irina, Larsson, Lars-Gunnar, Cetinkaya, Cihan, Hultquist, Anne, Su, Yingtao, Wu, Siqin, Bahram, Fuad, Påhlman, Sven, Guzhova, Irina, and Larsson, Lars-Gunnar

Abstract

The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN-gamma synergistically potentiates retinoic acid (RA)induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastorna cells with RA+IFN-gamma down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heteroclimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Madl/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA + IFN-gamma treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN-gamma and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma.

Published
2007
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21. The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential

Author

Luc, Sidinh, primary, Luis, Tiago C, additional, Boukarabila, Hanane, additional, Macaulay, Iain C, additional, Buza-Vidas, Natalija, additional, Bouriez-Jones, Tiphaine, additional, Lutteropp, Michael, additional, Woll, Petter S, additional, Loughran, Stephen J, additional, Mead, Adam J, additional, Hultquist, Anne, additional, Brown, John, additional, Mizukami, Takuo, additional, Matsuoka, Sahoko, additional, Ferry, Helen, additional, Anderson, Kristina, additional, Duarte, Sara, additional, Atkinson, Deborah, additional, Soneji, Shamit, additional, Domanski, Aniela, additional, Farley, Alison, additional, Sanjuan-Pla, Alejandra, additional, Carella, Cintia, additional, Patient, Roger, additional, de Bruijn, Marella, additional, Enver, Tariq, additional, Nerlov, Claus, additional, Blackburn, Clare, additional, Godin, Isabelle, additional, and Jacobsen, Sten Eirik W, additional

Published
2012
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22. Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD–induced myeloproliferation

Author

Kharazi, Shabnam, primary, Mead, Adam J., additional, Mansour, Anna, additional, Hultquist, Anne, additional, Böiers, Charlotta, additional, Luc, Sidinh, additional, Buza-Vidas, Natalija, additional, Ma, Zhi, additional, Ferry, Helen, additional, Atkinson, Debbie, additional, Reckzeh, Kristian, additional, Masson, Kristina, additional, Cammenga, Jörg, additional, Rönnstrand, Lars, additional, Arai, Fumio, additional, Suda, Toshio, additional, Nerlov, Claus, additional, Sitnicka, Ewa, additional, and Jacobsen, Sten Eirik W., additional

Published
2011
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24. Regulation and function of the Mad/Max/Myc network during neuronal and hematopoietic differentiation

Author

Hultquist, Anne and Hultquist, Anne

Abstract

The Mad/Max/Myc transcription factor network takes part in the control of vital cellular functions such as growth, proliferation, differentiation and apoptosis. Dimerization with the protein Max is necessary for the Myc-family of oncoproteins and their antagonists, the Mad-family proteins, to regulate target genes and carry out their intended functions. Myc functions as a positive regulator of proliferation, antagonized by the growth inhibitory Mad-proteins that potentially functions as tumor supprerssors. Deregulated Myc expression is found in a variety of tumors and signals negatively regulating Myc expression and/or activity could therefore be of potential use in treating tumors with deregulated Myc. Our aim was to therefore to investigate possible negative effects on Myc expression and activity by growth inhibitory cytokines and by the Myc antagonists, the Mad-family proteins.Two different cellular model systems of neuronal and hematopoietic origin have been utilized for these studies. Our results show that Mad1 is upregulated during induced neuronal differentiation of SH-SY5Y cells. Further, the growth inhibitory cytokine interferon-g (IFN-g) was shown to cooperate with retinoic acid (RA) and the phorbol ester TPA in inducing growth arrest and differentiation in N-myc amplified neuroblastoma cell lines. In contrast to treatment with either agent alone, the combined treatment of TPA+IFN-g and RA+IFN-g led to upregulation of Mad1 and to downregulation of N-Myc, respectively, thus correlating with the enhanced growth inhibition and differentiation observed after combination treatment. Ectopic expression of an inducible Mad1 in monoblastic U-937 cells led to growth inhibition but did not lead to differentiation or enhancement of differentiation induced by RA, vitamin D3 or TPA. In v-Myc transformed U-937 cells Mad1 expression reestablished the TPA-induced G1 cell cycle arrest, but did not restore differentiation, blocked by v-Myc. The growth inhibitory cytokine TGF

Published
2001

27. Identification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential

Author

Adolfsson, Jörgen, primary, Månsson, Robert, additional, Buza-Vidas, Natalija, additional, Hultquist, Anne, additional, Liuba, Karina, additional, Jensen, Christina T., additional, Bryder, David, additional, Yang, Liping, additional, Borge, Ole-Johan, additional, Thoren, Lina A.M., additional, Anderson, Kristina, additional, Sitnicka, Ewa, additional, Sasaki, Yutaka, additional, Sigvardsson, Mikael, additional, and Jacobsen, Sten Eirik W., additional

Published
2005
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32. PHF6Mutations Defines a Subgroup of Mixed Phenotype of Acute Leukemia with Aberrant T-Cell Differentiation

Author

Xiao, Wenbin, Pastore, Friederike, Getta, Bartlomiej, Hultquist, Anne, Shaffer, Brian C., Giralt, Sergio A., Rampal, Raajit K., Arcila, Maria E., Levine, Ross L., and Roshal, Mikhail

Abstract

Mixed phenotype acute leukemia (MPAL) is a rare form of acute leukemia, and comprises 2% of all acute leukemia diagnoses. With the exception of a small subset harboring BCR/ABL1 or MLL translocations (around 15% in combination), the genetic aberrations of MPAL are largely unknown. PHF6gene is located at Xq26-27 and encodes plant homeodomain finger 6, a zinc finger containing protein. Recurrent somatic PHF6mutations are frequent in T-ALL (up to 30%) and rarely in AML (~3%). Here we report recurrent PHF6mutations in approximately 20% of MPAL patients, making PHF6the most common genetic aberrations identified in MPAL.

Published
2017
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33. Identification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential: A Revised Road Map for Adult Blood Lineage Commitment.

Author

Adolfsson, Jörgen, Mânsson, Robert, Buza-Vidas, Natalija, Hultquist, Anne, Liuba, Karma, Jensen, Christina T., Bryder, David, Yang, Liping, Borge, Ole-Johan, Thoren, Lina A. M., Anderson, Krishna, Sitnicka, Ewa, Sasaki, Vutaka, Siqvardsson, Mikael, and Jacobsen, Sten Eirik W.

Subjects
*HEMATOPOIETIC stem cells, *CELL lines, *TYROSINE, *BLOOD, *T cells, *PROTEIN-tyrosine kinases
Abstract

All blood cell lineages derive from a common hematopoietic stem cell (HSC). The current model implicates that the first lineage commitment step of adult pluripotent HSCs results in a strict separation into common lymphoid and common myeloid precursors. We present evidence for a population of cells which, ala though sustaining a high proliferative and combined lympho-myeloid differentiation potential, have lost the ability to adopt erythroid and megakaryocyte lineage fates. Cells in the Lin-Sca-1+c-kit+ HSC compartment co-expressing high levels of the tyrosine kinase receptor Fit3- sustain granulocyte, monocyte, and B and T cell potentials but in contrast to Lin-Sca-1+c-kit+Fit3- HSCs fail to produce significant erythroid and megakaryocytic progeny. This distinct lineage restriction site is accompanied by down regulation of genes for regulators of erythroid and megakaryocyte development. In agreement with representing a lymphoid primed progenitor, Lit-Sca-1+c-kit+CD34+Fit3- cells display upregulated IL-7 receptor gene expression. Based on these observations, we propose a revised road map for adult blood lineage development. [ABSTRACT FROM AUTHOR]

Published
2005
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34. TGF-beta enforces senescence in Myc-transformed hematopoietic tumor cells through induction of Mad1 and repression of Myc activity.

Author

Wu S, Hultquist A, Hydbring P, Cetinkaya C, Oberg F, and Larsson LG

Subjects
Cell Cycle physiology, Cell Cycle Proteins genetics, Cell Line, Tumor, Gene Knockdown Techniques, Hematologic Neoplasms metabolism, Humans, Myeloid Cells metabolism, Nuclear Proteins genetics, RNA, Small Interfering metabolism, Cell Cycle Proteins metabolism, Cellular Senescence, Hematologic Neoplasms pathology, Myeloid Cells physiology, Nuclear Proteins metabolism, Proto-Oncogene Proteins c-myc metabolism, Transforming Growth Factor beta1 metabolism
Abstract

Inhibition of tumor growth factor (TGF)-beta-mediated cell cycle exit is considered an important tumorigenic function of Myc oncoproteins. Here we found that TGF-beta1 enforced G(1) cell cycle arrest and cellular senescence in human U-937 myeloid tumor cells ectopically expressing v-Myc, which contains a stabilizing mutation frequently found in lymphomas. This correlated with induced expression of the Myc antagonist Mad1, resulting in replacement of Myc for Mad1 at target promoters, reduced histone acetylation and strong repression of Myc-driven transcription. The latter was partially reversed by histone deacetylase (HDAC) inhibitors, consistent with involvement of Mad1. Importantly, knockdown of MAD1 expression prevented TGF-beta1-induced senescence, underscoring that Mad1 is a crucial component of this process. Enforced Mad1 expression sensitized U-937-myc cells to TGF-beta and restored phorbol ester-induced cell cycle exit, but could not alone induce G(1) arrest, suggesting that Mad1 is required but not sufficient for cellular senescence. Our results thus demonstrate that TGF-beta can override Myc activity despite a stabilizing cancer mutation and induce senescence in myeloid tumor cells, at least in part by induction of Mad1. TGF-beta-induced senescence, or signals mimicking this pathway, could therefore potentially be explored as a therapeutic principle for treating hematopoietic and other tumors with deregulated MYC expression.

Published
2009
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35. Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells.

Author

Cetinkaya C, Hultquist A, Su Y, Wu S, Bahram F, Påhlman S, Guzhova I, and Larsson LG

Subjects
Acetylation, Blotting, Northern, Blotting, Western, Cell Cycle Proteins genetics, Cell Differentiation drug effects, Chromatin metabolism, Chromatin Immunoprecipitation, Dimerization, Drug Therapy, Combination, Gene Expression Regulation, Neoplastic, Histones metabolism, Humans, Immunoprecipitation, Interferon-gamma therapeutic use, N-Myc Proto-Oncogene Protein, Neuroblastoma metabolism, Neuroblastoma pathology, Nuclear Proteins genetics, Ornithine Decarboxylase genetics, Ornithine Decarboxylase metabolism, Proto-Oncogene Proteins c-myc antagonists & inhibitors, RNA, Messenger genetics, RNA, Messenger metabolism, Repressor Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tretinoin therapeutic use, Tumor Cells, Cultured, Antineoplastic Agents therapeutic use, Basic-Leucine Zipper Transcription Factors metabolism, Cell Cycle Proteins metabolism, Neuroblastoma drug therapy, Nuclear Proteins metabolism, Oncogene Proteins metabolism, Proto-Oncogene Proteins c-myc metabolism
Abstract

The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN-gamma synergistically potentiates retinoic acid (RA)-induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastoma cells with RA+IFN-gamma down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heterodimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Mad1/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA+IFN-gamma treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN-gamma and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma.

Published
2007
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