Myelodysplastic syndrome (MDS) with interstitial deletion of a segment of the long arm of chromosome 5q [del(5q)] is characterized by bone marrow erythroid hyperplasia, atypical megakaryocytes, thrombocythemia, refractory anemia, and low risk of progression to acute myeloid leukemia (AML) compared with other types of MDS. The long arm of chromosome 5 contains two distinct commonly deleted regions (CDRs). The more distal CDR lies in 5q33.1 and contains 40 protein-coding genes and genes coding microRNAs (miR-143, miR-145). In 5q-syndrome one allele is deleted that accounts for haploinsufficiency of these genes. The mechanism of erythroid failure appears to involve the decreased expression of the ribosomal protein S14 (RPS14) gene and the upregulation of the p53 pathway by ribosomal stress. Friend leukemia virus integration 1 (Fli1) is one of the target genes of miR145. Increased Fli1 expression enables effective megakaryopoiesis in 5q-syndrome. 1. Introduction Approximately 15% of patients with MDS have abnormalities of chromosome 5 [1]. These abnormalities include interstitial deletion of a segment of the long arm of chromosome 5q [del(5q), 5q-syndrome], monosomy, and unbalanced translocations. 5q-syndrome as MDS category was defined by the World Health Organization (WHO) [2], and it is characterized by refractory macrocytic anemia with dyserythropoiesis, transfusion dependence, normal to elevated platelet counts, hypolobated and nonlobated megakaryocytes, female preponderance, a favourable prognosis, and low risk of progression to AML compared with other types of MDS [3–10]. Many research groups analysed chromosome 5q deletions in patients with 5q-syndrome. We will shortly describe these studies from historical point of view and not for relevance in the pathogenesis. Deletion of interferon regulatory factor-1 gene (IRF1) mapped to chromosome 5q31 was detected [11]. IRF1 is a putative tumor suppressor and a transcriptional activator of interferon and interferon-stimulated genes. IRF1 dosage experiments demonstrated that 2 patients with 5q-syndrome retained both copies of this gene [12]. Thus, IRF1 maps outside the common deleted segment of the 5q-chromosome, and the same result was obtained in the case of EGR1 (epidermal growth receptor 1) [13, 14]. Molecular mapping techniques defined the region of gene loss in two patients with the 5q-syndrome and uncharacteristically small 5q deletions (5q31–q33) [14]. The allelic loss of 10 genes localized to 5q23-qter [centromere-CSF2 (colony-stimulating factor 2/granulocyte-macrophage/)-EGR1 (early growth
References
[1]
D. Haase, U. Germing, J. Schanz 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, vol. 110, no. 13, pp. 4385–4395, 2007.
[2]
R. P. Hasserjian, M. M. Le Beau, A. F. List, et al., WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues, International Agency for Research on Cancer Press, Lyon, France, 2007.
[3]
H. Van Den Berghe, J. J. Cassiman, and G. David, “Distinct haematological disorder with deletion of long arm of No. 5 chromosome,” Nature, vol. 251, no. 5474, pp. 437–438, 1974.
[4]
H. Van Den Berghe, K. Vermaelen, and C. Mecucci, “The 5q- anomaly,” Cancer Genetics and Cytogenetics, vol. 17, no. 3, pp. 189–255, 1985.
[5]
S. D. Nimer and D. W. Golde, “The 5q-abnormality,” Blood, vol. 70, no. 6, pp. 1705–1712, 1987.
[6]
P. Mathew, A. Tefferi, G. W. Dewald et al., “The 5q- syndrome: a single-institution study of 43 consecutive patients,” Blood, vol. 81, no. 4, pp. 1040–1045, 1993.
[7]
J. Boultwood, S. Lewis, and J. S. Wainscoat, “The 5q- syndrome,” Blood, vol. 84, no. 10, pp. 3253–3260, 1994.
[8]
H. Van Den Berghe and L. Michaux, “5q-, twenty-five years later: a synopsis,” Cancer Genetics and Cytogenetics, vol. 94, no. 1, pp. 1–7, 1997.
[9]
A. A. N. Giagounidis, U. Germing, J. S. Wainscoat, J. Boultwood, and C. Aul, “The 5q-syndrome,” Hematology, vol. 9, no. 4, pp. 271–277, 2004.
[10]
A. Mohamedali and G. J. Mufti, “Van-den Berghe's 5q- syndrome in 2008,” British Journal of Haematology, vol. 144, no. 2, pp. 157–168, 2009.
[11]
C. L. Willman, C. E. Sever, M. G. Pallavicini et al., “Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia,” Science, vol. 259, no. 5097, pp. 968–971, 1993.
[12]
J. Boultwood, C. Fidler, S. Lewis et al., “Allelic loss of IRF1 in myelodysplasia and acute myeloid leukemia: retention of IRF1 on the 5q- chromosome in some patients with the 5q- syndrome,” Blood, vol. 82, no. 9, pp. 2611–2616, 1993.
[13]
M. M. Le Beau, R. Espinosa, W. L. Neuman et al., “Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 12, pp. 5484–5488, 1993.
[14]
J. Boultwood, C. Fidler, S. Lewis et al., “Molecular mapping of uncharacteristically small 5q deletions in two patients with the 5q- syndrome: delineation of the critical region on 5q and identification of a 5q- breakpoint,” Genomics, vol. 19, no. 3, pp. 425–432, 1994.
[15]
J. Boultwood, C. Fidler, A. J. Strickson et al., “Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome,” Blood, vol. 99, no. 12, pp. 4638–4641, 2002.
[16]
R. J. Jaju, J. Boultwood, F. J. Oliveret, et al., “Molecular cytogenc definition of the critical deleted region in the 5q- syndrome,” Genes Chromosomes Cancer, vol. 22, pp. 251–256, 1998.
[17]
N. Zhao, A. Stoffel, P. W. Wang et al., “Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1-1.5 Mb and preparation of a PAC-based physical map,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 13, pp. 6948–6953, 1997.
[18]
M. L. Heaney and D. W. Golde, “Myelodysplasia,” The New England Journal of Medicine, vol. 340, no. 21, pp. 1649–1660, 1999.
[19]
L. Nilsson, I. Astrand-Grundstrom, I. Arvidsson et al., “Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level,” Blood, vol. 96, no. 6, pp. 2012–2021, 2000.
[20]
K. M. Eisenmann, K. J. Dykema, S. F. Matheson et al., “5q- myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics,” Oncogene, vol. 28, no. 39, pp. 3429–3441, 2009.
[21]
J. Boultwood, A. Pellagatti, H. Cattan et al., “Gene expression profiling of CD34+ cells in patients with the 5q- syndrome,” British Journal of Haematology, vol. 139, no. 4, pp. 578–589, 2007.
[22]
A. G. Knudson, “Mutation and cancer: statistical study of retinoblastoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 68, no. 4, pp. 820–823, 1971.
[23]
A. J. W. Paige, “Redefining tumour suppressor genes: exceptions to the two-hit hypothesis,” Cellular and Molecular Life Sciences, vol. 60, no. 10, pp. 2147–2163, 2003.
[24]
B. L. Ebert, “Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer,” Leukemia, vol. 23, no. 7, pp. 1252–1256, 2009.
[25]
A. Narla and B. L. Ebert, “Ribosomopathies: human disorders of ribosome dysfunction,” Blood, vol. 115, no. 16, pp. 3196–3205, 2010.
[26]
M. Tormo, I. Marugán, and M. Calabuig, “Myelodysplastic syndromes: an update on molecular pathology,” Clinical and Translational Oncology, vol. 12, no. 10, pp. 652–661, 2010.
[27]
M. S. Davids and D. P. Steensma, “The molecular pathogenesis of myelodysplastic syndromes,” Cancer Biology and Therapy, vol. 10, no. 4, pp. 309–319, 2010.
[28]
A. H. Berger and P. P. Pandolfi, “Haplo-insufficiency: a driving force in cancer,” Journal of Pathology, vol. 223, no. 2, pp. 137–146, 2011.
[29]
P. Montaville, Y. Dai, C. Y. Cheung et al., “Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22,” Biochimica et Biophysica Acta, vol. 1763, no. 11, pp. 1335–1343, 2006.
[30]
J. Jia, C. Tong, B. Wang, L. Luo, and J. Jiang, “Hedgehog signalling activity of smoothened requires phosphorylation by protein kinase A and casein kinase I,” Nature, vol. 432, no. 7020, pp. 1045–1050, 2004.
[31]
A. H？mmerlein, J. Weiske, and O. Huber, “A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor-1/β-catenin complex,” Cellular and Molecular Life Sciences, vol. 62, no. 5, pp. 606–618, 2005.
[32]
S. Lehmann, J. O'Kelly, S. Raynaud, S. E. Funk, E. H. Sage, and H. P. Koeffler, “Common deleted genes in the 5q-syndrome: thrombocytopenia and reduced erythroid colony formation in SPARC null mice,” Leukemia, vol. 21, no. 9, pp. 1931–1936, 2007.
[33]
B. L. Ebert, J. Pretz, J. Bosco et al., “Identification of RPS14 as a 5q- syndrome gene by RNA interference screen,” Nature, vol. 451, no. 7176, pp. 335–339, 2008.
[34]
S. R. Ellis and P. E. Gleizes, “Diamond Blackfan anemia: ribosomal proteins going rogue,” Seminars in Hematology, vol. 48, pp. 89–96, 2011.
[35]
A. Valencia, J. Cervera, E. Such, M. A. Sanz, and G. F. Sanz, “Lack of RPS14 promoter aberrant methylation supports the haploinsufficiency model for the 5q- Syndrome,” Blood, vol. 112, no. 3, p. 918, 2008.
[36]
N. Draptchinskaia, P. Gustavsson, B. Andersson et al., “The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia,” Nature Genetics, vol. 21, no. 2, pp. 169–175, 1999.
[37]
H. T. Gazda, A. Grabowska, L. B. Merida-Long et al., “Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia,” American Journal of Human Genetics, vol. 79, no. 6, pp. 1110–1118, 2006.
[38]
K. A. Ganapathi and A. Shimamura, “Ribosomal dysfunction and inherited marrow failure,” British Journal of Haematology, vol. 141, no. 3, pp. 376–387, 2008.
[39]
M. F. Campagnoli, U. Ramenghi, M. Armiraglio et al., “RPS19 mutations in patients with Diamond-Blackfan anemia,” Human Mutation, vol. 29, no. 7, pp. 911–920, 2008.
[40]
R. Cmejla, J. Cmejlova, H. Handrkova et al., “Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with diamond-blackfan anemia,” Human Mutation, vol. 30, no. 3, pp. 321–327, 2009.
[41]
J. M. Lipton and S. R. Ellis, “Diamond-blackfan anemia: diagnosis, treatment, and molecular pathogenesis,” Hematology/Oncology Clinics of North America, vol. 23, no. 2, pp. 261–282, 2009.
[42]
L. Doherty, M. R. Sheen, A. Vlachos et al., “Ribosomal protein genes RPS10 and RPS26 are commonly mutated in diamond-blackfan anemia,” American Journal of Human Genetics, vol. 86, no. 2, pp. 222–228, 2010.
[43]
E. E. Devlin, L. DaCosta, N. Mohandas, G. Elliott, and D. M. Bodine, “A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia,” Blood, vol. 116, no. 15, pp. 2826–2835, 2010.
[44]
J. Hoefele, A. M. Bertrand, M. Stehr et al., “Disorders of sex development and Diamond-Blackfan anemia: is there an association?” Pediatric Nephrology, vol. 25, no. 7, pp. 1255–1261, 2010.
[45]
E. Ito, Y. Konno, T. Toki, and K. Terui, “Molecular pathogenesis in Diamond-Blackfan anemia,” International Journal of Hematology, vol. 92, no. 3, pp. 413–418, 2010.
[46]
I. Boria, E. Garelli, H. T. Gazda et al., “The ribosomal basis of diamond-blackfan anemia: mutation and database update,” Human Mutation, vol. 31, no. 12, pp. 1269–1279, 2010.
[47]
H. W. Josephs, “Anemia of infancy and early childhood,” Medicine, vol. 15, pp. 307–451, 1936.
[48]
L. K. Diamond and K. D. Blackfan, “Hypoplastic anemia,” Am. J. Dis. Child., vol. 56, pp. 464–467, 1938.
[49]
J. L. Barlow, L. F. Drynan, D. R. Hewett et al., “A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome,” Nature Medicine, vol. 16, no. 1, pp. 59–66, 2010.
[50]
A. Pellagatti, E. Hellstr？m-Lindberg, A. Giagounidis et al., “Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes,” British Journal of Haematology, vol. 142, no. 1, pp. 57–64, 2008.
[51]
H. T. Gazda, A. T. Kho, D. Sanoudou et al., “Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia,” Stem Cells, vol. 24, no. 9, pp. 2034–2044, 2006.
[52]
K. Sridhar, D. T. Ross, R. Tibshirani, A. J. Butte, and P. L. Greenberg, “Relationship of differential gene expression profiles in CD34+ myelodysplastic syndrome marrow cells to disease subtype and progression,” Blood, vol. 114, no. 23, pp. 4847–4858, 2009.
[53]
H. He and Y. Sun, “Ribosomal protein S27L is a direct p53 target that regulates apoptosis,” Oncogene, vol. 26, no. 19, pp. 2707–2716, 2007.
[54]
J. Li, J. Tan, L. Zhuang et al., “Ribosomal protein S27-like, a p53-inducible modulator of cell fate in response to genotoxic stress,” Cancer Research, vol. 67, no. 23, pp. 11317–11326, 2007.
[55]
M. J. Farquhar and D. T. Bowen, “Oxidative stress and the myelodysplastic syndromes,” International Journal of Hematology, vol. 77, no. 4, pp. 342–350, 2003.
[56]
H. Ghoti, J. Amer, A. Winder, E. Rachmilewitz, and E. Fibach, “Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome,” European Journal of Haematology, vol. 79, no. 6, pp. 463–467, 2007.
[57]
B. Novotna, Y. Bagryantseva, M. Siskova, and R. Neuwirtova, “Oxidative DNA damage in bone marrow cells of patients with low-risk myelodysplastic syndrome,” Leukemia Research, vol. 33, no. 2, pp. 340–343, 2009.
[58]
D. P. Bartel, “MicroRNAs: target recognition and regulatory functions,” Cell, vol. 136, no. 2, pp. 215–233, 2009.
[59]
D. T. Starczynowski, F. Kuchenbauer, B. Argiropoulos et al., “Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype,” Nature Medicine, vol. 16, no. 1, pp. 49–58, 2010.
[60]
E. Terpos, E. Verrou, A. Banti, V. Kaloutsi, A. Lazaridou, and K. Zervas, “Bortezomib is an effective agent for MDS/MPD syndrome with 5q- anomaly and thrombocytosis,” Leukemia Research, vol. 31, no. 4, pp. 559–562, 2007.
[61]
D. T. Starczynowski, R. Morin, A. McPherson, et al., “Genome-wide identification of human microRNAs located in leukemia-associated genomic alterations,” Blood, vol. 117, pp. 595–607, 2011.
[62]
M. Kumar, A. Narla, A. Nonami, et al., “Coordinate 1oss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome,” Blood, vol. 118, pp. 4663–4673, 2011.
[63]
J. Boultwood, A. Pellagatti, A. N. J. McKenzie, and J. S. Wainscoat, “Advances in the 5q-syndrome,” Blood, vol. 116, no. 26, pp. 5803–5811, 2010.
[64]
H. Votavova, M. Grmanova, M. Dostalova Merkerova et al., “Differential expression of microRNAs in CD34+ cells of 5q- syndrome,” Journal of Hematology and Oncology, vol. 4, p. 1, 2011.
[65]
H. I. Suzuki, K. Yamagata, K. Sugimoto, T. Iwamoto, S. Kato, and K. Miyazono, “Modulation of microRNA processing by p53,” Nature, vol. 460, no. 7254, pp. 529–533, 2009.
[66]
L. Boominathan, “The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network,” Cancer and Metastasis Reviews, vol. 29, no. 4, pp. 613–639, 2010.
[67]
M. Ozen, C. J. Creighton, M. Ozdemir, and M. Ittmann, “Widespread deregulation of microRNA expression in human prostate cancer,” Oncogene, vol. 27, no. 12, pp. 1788–1793, 2008.
[68]
Y. Wang and C. G. L. Lee, “MicroRNA and cancer—focus on apoptosis,” Journal of Cellular and Molecular Medicine, vol. 13, no. 1, pp. 12–23, 2009.
[69]
Y. Akao, Y. Nakagawa, and T. Naoe, “MicroRNA-143 and -145 in colon cancer,” DNA and Cell Biology, vol. 26, no. 5, pp. 311–320, 2007.
[70]
M. Sachdeva and Y. Y. Mo, “miR-145-mediated suppression of cell growth, invasion and metastasis,” American Journal of Translational Research, vol. 2, no. 2, pp. 170–180, 2010.
[71]
J. Zhang, H. Guo, H. Zhang, et al., “Putative tumor suppressor miR-145 inhibits colon cancer cell growth by targeting oncogene friend leukemia virus integration 1 gene,” Cancer, vol. 117, no. 1, pp. 86–95, 2011.
[72]
B. Shi, L. Sepp-Lorenzino, M. Prisco, P. Linsley, T. Deangelis, and R. Baserga, “Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells,” Journal of Biological Chemistry, vol. 282, no. 45, pp. 32582–32590, 2007.
[73]
J. Zhang, H. Guo, G. Qian et al., “MiR-145, a new regulator of the DNA Fragmentation Factor-45 (DFF45)-mediated apoptotic network,” Molecular Cancer, vol. 9, article 211, 2010.
[74]
C. C. Chiu, C. H. M. Y. Lin, and K. Fang, “Etoposide (VP-16) sensitizes p53-deficient human non-small cell lung cancer cells to caspase-7-mediated apoptosis,” Apoptosis, vol. 10, no. 3, pp. 643–650, 2005.
[75]
X. Liu, H. Zou, C. Slaughter, and X. Wang, “DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis,” Cell, vol. 89, no. 2, pp. 175–184, 1997.
[76]
A. E. Williams, M. M. Perry, S. A. Moschos, H. M. Larner-Svensson, and M. A. Lindsay, “Role of miRNA-146a in the regulation of the innate immune response and cancer,” Biochemical Society Transactions, vol. 36, no. 6, pp. 1211–1215, 2008.
[77]
L. Li, X.-P. Chen, and Y.-J. Li, “MicroRNA-146a and human disease,” Scandinavian Journal of Immunology, vol. 71, pp. 227–231, 2010.
[78]
D. T. Starczynowski, F. Kuchenbauer, and J. Wegrzyn, “MicroRNA-146a disrupts hematopoietic differentiation and survival,” Experimental Hematology, vol. 39, pp. 167–178, 2011.
[79]
K. R. Cordes, N. T. Sheehy, M. P. White et al., “MiR-145 and miR-143 regulate smooth muscle cell fate and plasticity,” Nature, vol. 460, no. 7256, pp. 705–710, 2009.
[80]
T. Boettger, N. Beetz, S. Kostin et al., “Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster,” Journal of Clinical Investigation, vol. 119, no. 9, pp. 2634–2647, 2009.
[81]
M. Dostalova Merkerova, Z. Krejcik, H. Votavova, M. Belickova, A. Vasikova, and J. Cermak, “Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome,” European Journal of Human Genetics, vol. 19, pp. 313–319, 2011.
[82]
L. Pani？, J. Montagne, M. Cokari？, and S. Volarevi？, “S6-haploinsufficiency activates the p53 tumor suppressor,” Cell Cycle, vol. 6, no. 1, pp. 20–24, 2007.
[83]
N. Danilova, K. M. Sakamoto, and S. Lin, “Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family,” Blood, vol. 112, no. 13, pp. 5228–5237, 2008.
[84]
N. C. Jones, M. L. Lynn, K. Gaudenz et al., “Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function,” Nature Medicine, vol. 14, no. 2, pp. 125–133, 2008.
[85]
K. A. McGowan, J. Z. Li, C. Y. Park et al., “Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects,” Nature Genetics, vol. 40, no. 8, pp. 963–970, 2008.
[86]
M. Barki？, S. Crnomarkovi？, K. Grabu？i？ et al., “The p53 tumor suppressor causes congenital malformations in Rpl24-deficient mice and promotes their survival,” Molecular and Cellular Biology, vol. 29, no. 10, pp. 2489–2504, 2009.
[87]
C. Constantinou, A. Elia, and M. J. Clemens, “Activation of p53 stimulates proteasome-dependent truncation of elF4E-binding protein 1 (4E-BP1),” Biology of the Cell, vol. 100, no. 5, pp. 279–289, 2008.
[88]
J. Momand, H. H. Wu, and G. Dasgupta, “MDM2-master regulator of the p53 tumor suppressor protein,” Gene, vol. 242, no. 1-2, pp. 15–29, 2000.
[89]
S. Fang, J. P. Jensen, R. L. Ludwig, K. H. Vousden, and A. M. Weissman, “Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53,” Journal of Biological Chemistry, vol. 275, no. 12, pp. 8945–8951, 2000.
[90]
H. V. Clegg, K. Itahana, and Y. Zhang, “Unlocking the Mdm2-p53 loop: ubiquitin is the key,” Cell Cycle, vol. 7, no. 3, pp. 287–292, 2008.
[91]
M. S. Dai and H. Lu, “Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5,” Journal of Biological Chemistry, vol. 279, no. 43, pp. 44475–44482, 2004.
[92]
M. A. E. Lohrum, R. L. Ludwig, M. H. G. Kubbutat, M. Hanlon, and K. H. Vousden, “Regulation of HDM2 activity by the ribosomal protein L11,” Cancer Cell, vol. 3, no. 6, pp. 577–587, 2003.
[93]
Y. Zhang, G. W. Wolf, K. Bhat et al., “Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway,” Molecular and Cellular Biology, vol. 23, no. 23, pp. 8902–8912, 2003.
[94]
K. P. Bhat, K. Itahana, A. Jin, and Y. Zhang, “Essential role of ribosomal protein L11 in mediating growth inhibition-induced p53 activation,” EMBO Journal, vol. 23, no. 12, pp. 2402–2412, 2004.
[95]
M. S. Dai, S. X. Zeng, Y. Jin, X. X. Sun, L. David, and H. Lu, “Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition,” Molecular and Cellular Biology, vol. 24, no. 17, pp. 7654–7668, 2004.
[96]
Y. Ofir-Rosenfeld, K. Boggs, D. Michael, M. B. Kastan, and M. Oren, “Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26,” Molecular Cell, vol. 32, no. 2, pp. 180–189, 2008.
[97]
D. Chen, Z. Zhang, M. Li et al., “Ribosomal protein S7 as a novel modulator of p53-MDM2 interaction: binding to MDM2, stabilization of p53 protein, and activation of p53 function,” Oncogene, vol. 26, no. 35, pp. 5029–5037, 2007.
[98]
Y. Zhang and H. Lu, “Signaling to p53: ribosomal proteins find their way,” Cancer Cell, vol. 16, no. 5, pp. 369–377, 2009.
[99]
Y. Zhang, J. Wang, Y. Yuan et al., “Negative regulation of HDM2 to attenuate p53 degradation by ribosomal protein L26,” Nucleic Acids Research, vol. 38, no. 19, Article ID gkq536, pp. 6544–6554, 2010.
[100]
D. G. Pestov, Z. Strezoska, and L. F. Lau, “Evidence of p53-dependent cross-talk between ribosome biogenesis and the cell cycle: effects of nucleolar protein Bop1 on G1/S transition,” Molecular and Cellular Biology, vol. 21, no. 13, pp. 4246–4255, 2001.
[101]
C. Deisenroth and Y. Zhang, “Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway,” Oncogene, vol. 29, no. 30, pp. 4253–4260, 2010.
[102]
D. M. Gilkes, L. Chen, and J. Chen, “MDMX regulation of p53 response to ribosomal stress,” EMBO Journal, vol. 25, no. 23, pp. 5614–5625, 2006.
[103]
X. X. Sun, Y. G. Wang, D. P. Xirodimas, and M. S. Dai, “Perturbation of 60 S ribosomal biogenesis results in ribosomal protein L5- and L11-dependent p53 activation,” Journal of Biological Chemistry, vol. 285, no. 33, pp. 25812–25821, 2010.
[104]
A. Pellagatti, T. Marafioti, J. C. Paterson et al., “Induction of p53 and up-regulation of the p53 pathway in the human 5q- syndrome,” Blood, vol. 115, no. 13, pp. 2721–2723, 2010.
[105]
M. E. Perry, “The regulation of the p53-mediated stress response by MDM2 and MDM4,” Cold Spring Harbor Perspectives in Biology, vol. 2, no. 1, article a000968, 2010.
[106]
J. S. L. Ho, W. Ma, D. Y. L. Mao, and S. Benchimol, “p53-dependent transcriptional repression of c-myc is required for G 1 cell cycle arrest,” Molecular and Cellular Biology, vol. 25, no. 17, pp. 7423–7431, 2005.
[107]
M. Sachdeva, S. Zhu, F. Wu et al., “p53 represses c-Myc through induction of the tumor suppressor miR-145,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 9, pp. 3207–3212, 2009.
[108]
M. Sachdeva and Y. Y. Mo, “p53 and c-myc: how does the cell balance "yin" and "yang"?” Cell Cycle, vol. 8, no. 9, p. 1303, 2009.
[109]
A. H. L. Truong, D. Cervi, J. Lee, and Y. Ben-David, “Direct transcriptional regulation of MDM2 by Fli-1,” Oncogene, vol. 24, no. 6, pp. 962–969, 2005.
[110]
D. H. Christiansen, M. K. Andersen, and J. Pedersen-Bjergaard, “Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis,” Journal of Clinical Oncology, vol. 19, no. 5, pp. 1405–1413, 2001.
[111]
J. Pedersen-Bjergaard, M. K. Andersen, M. T. Andersen, and D. H. Christiansen, “Genetics of therapy-related myelodysplasia and acute myeloid leukemia,” Leukemia, vol. 22, no. 2, pp. 240–248, 2008.
[112]
M. J？dersten, L. Saft, A. Pellagatti et al., “Clonal heterogeneity in the 5q- syndrome: P53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression,” Haematologica, vol. 94, no. 12, pp. 1762–1766, 2009.
[113]
M. J？dersten, L. Saft, A. Smith, et al., “TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict dinase progression,” Journal of Clinical Oncology, vol. 29, pp. 1971–1979, 2011.
[114]
C. M. Lim, M. A. Cater, J. F. B. Mercer, and S. La Fontaine, “Copper-dependent interaction of dynactin subunit p62 with the N terminus of ATP7B but not ATP7A,” Journal of Biological Chemistry, vol. 281, no. 20, pp. 14006–14014, 2006.
[115]
S. R. Patel, J. L. Richardson, H. Schulze et al., “Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes,” Blood, vol. 106, no. 13, pp. 4076–4085, 2005.
[116]
J. E. Italiano Jr., S. Patel-Hett, and J. H. Hartwig, “Mechanics of proplatelet elaboration,” Journal of Thrombosis and Haemostasis, vol. 5, supplement 1, pp. 18–23, 2007.
[117]
F. He, C. T. Wang, and L. T. Gou, “RNA-binding motif protein RBM22 is required for normal development of zebrafish embryos,” Genetics and Molecular Research, vol. 8, no. 4, pp. 1466–1473, 2009.
[118]
S. Grisendi, R. Bernardi, M. Rossi et al., “Role of nucleophosmin in embryonic development and tumorigenesis,” Nature, vol. 437, no. 7055, pp. 147–153, 2005.
[119]
S. Grisendi, C. Mecucci, B. Falini, and P. P. Pandolfi, “Nucleophosmin and cancer,” Nature Reviews Cancer, vol. 6, no. 7, pp. 493–505, 2006.
[120]
P. Sportoletti, S. Grisendi, S. M. Majid et al., “Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse,” Blood, vol. 111, no. 7, pp. 3859–3862, 2008.
[121]
G. Cazzaniga, M. G. Dell'Oro, C. Mecucci et al., “Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype,” Blood, vol. 106, no. 4, pp. 1419–1422, 2005.
[122]
R. Rau and P. Brown, “Nucleophosmin (NPM1) mutations in adult and childhood acute myeloid leukaemia: towards definition of a new leukaemia entity,” Hematological Oncology, vol. 27, no. 4, pp. 171–181, 2009.
[123]
M. J. Walter, “Del(5q): gene dosage matters,” Blood, vol. 110, no. 2, pp. 473–474, 2007.
[124]
R. Neuwirtova, O. Fuchs, D. Provaznikova, et al., “Fli-1 and EKLF gene expression in patients with MDS 5q- syndrome,” Blood, vol. 114, pp. 1090–1091, 2009, abstract no. 2788, Proceedings of the 51st Annual Meeting of the American Society of Hematology, December 5–8, 2009, New Orleans, La, USA.
[125]
R. Neuwirtova, O. Fuchs, A. Jonasova, et al., “The role of Fli-1 and EKLF gene expression in 5q- syndrome compared to MDS low risk with normal chromosome 5,” in Proceedings of the XXXIII World Congress of the International Society of Hematology, Jerusalem, Israel, abstract no. 114, October 2010.
[126]
Y. Ben-David, E. B. Giddens, K. Letwin, and A. Bernstein, “Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1,” Genes and Development, vol. 5, no. 6, pp. 908–918, 1991.
[127]
D. K. Watson, F. E. Smyth, D. M. Thompson et al., “The ERGB/Fli-1 gene: isolation and characterization of a new member of the family of human ETS transcription factors,” Cell Growth and Differentiation, vol. 3, no. 10, pp. 705–713, 1992.
[128]
D. D. K. Prasad, V. N. Rao, and E. S. P. Reddy, “Structure and expression of human Fli-1 gene,” Cancer Research, vol. 52, no. 20, pp. 5833–5837, 1992.
[129]
L. Selleri, M. Giovannini, A. Romo et al., “Cloning of the entire FLI1 gene, disrupted by the Ewing's sarcoma translocation breakpoint on 11q24, in a yeast artificial chromosome,” Cytogenetics and Cell Genetics, vol. 67, no. 2, pp. 129–136, 1994.
[130]
J. Starck, N. Cohet, C. Gonnet et al., “Functional cross-antagonism between transcription factors FLI-1 and EKLF,” Molecular and Cellular Biology, vol. 23, no. 4, pp. 1390–1402, 2003.
[131]
M. Eisbacher, M. L. Holmes, A. Newton et al., “Protein-protein interaction between Fli-1 and GATA-1 mediates synergistic expression of megakaryocyte-specific genes through cooperative DNA binding,” Molecular and Cellular Biology, vol. 23, no. 10, pp. 3427–3441, 2003.
[132]
P. Jackers, G. Szalai, O. Moussa, and D. K. Watson, “Ets-dependent regulation of target gene expression during megakaryopoiesis,” Journal of Biological Chemistry, vol. 279, no. 50, pp. 52183–52190, 2004.
[133]
J. L. Svenson, K. Chike-Harris, M. Y. Amria, and T. K. Nowling, “The mouse and human Fli1 genes are similarly regulated by Ets factors in T cells,” Genes and Immunity, vol. 11, no. 2, pp. 161–172, 2010.
[134]
J. Starck, A. Doubeikovski, S. Sarrazin et al., “Spi-1/PU.1 Is a positive regulator of the Fli-1 gene involved in inhibition of erythroid differentiation in friend erythroleukemic cell lines,” Molecular and Cellular Biology, vol. 19, no. 1, pp. 121–135, 1999.
[135]
N. Rekhtman, F. Radparvar, T. Evans, and A. I. Skoultchi, “Direct interaction of hematopoietic transcription factors PU.1 and GATA- 1: functional antagonism in erythroid cells,” Genes and Development, vol. 13, no. 11, pp. 1398–1411, 1999.
[136]
P. Zhang, X. Zhang, A. Iwama et al., “PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding,” Blood, vol. 96, no. 8, pp. 2641–2648, 2000.
[137]
G. Juban, G. Giraud, B. Guyot et al., “Spi-1 and Fli-1 directly activate common target genes involved in ribosome biogenesis in friend erythroleukemic cells,” Molecular and Cellular Biology, vol. 29, no. 10, pp. 2852–2864, 2009.
[138]
D. T. Starczynowski and A. Karsan, “Innate immune signaling in the myelodysplastic syndromes,” Hematology/Oncology Clinics of North America, vol. 24, pp. 343–359, 2010.
[139]
D. R. Hodge, W. Xiao, P. A. Clausen, G. Heidecker, M. Szyf, and W. L. Farrar, “Interleukin-6 regulation of the human DNA methyltransferase (HDNMT) gene in human erythroleukemia cells,” Journal of Biological Chemistry, vol. 276, no. 43, pp. 39508–39511, 2001.
[140]
D. R. Hodge, D. Li, S. M. Qi, and W. L. Farrar, “IL-6 induces expression of the Fli-1 proto-oncogene via STAT3,” Biochemical and Biophysical Research Communications, vol. 292, pp. 287–291, 2002.
[141]
M. R. Tallack, T. Whitington, W. S. Yuen et al., “A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells,” Genome Research, vol. 20, no. 8, pp. 1052–1063, 2010.
[142]
M. Siatecka and J. J. Bieker, “The multifunctional role of EKLF/KLF1 during erythropoiesis,” Blood, vol. 118, pp. 2044–2054, 2011.
[143]
L. C. Doré and J. D. Crispino, “Transcription factor in erythroid cell and megakaryocyte development,” Blood, vol. 118, pp. 231–239, 2011.
[144]
J. Borg, P. Papadopoulos, M. Georgitsi et al., “Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin,” Nature Genetics, vol. 42, no. 9, pp. 801–805, 2010.
[145]
P. Frontelo, D. Manwani, M. Galdass et al., “Novel role for EKLF in megakaryocyte lineage commitment,” Blood, vol. 110, no. 12, pp. 3871–3880, 2007.
[146]
F. Bouilloux, G. Juban, N. Cohet et al., “EKLF restricts megakaryocytic differentiation at the benefit of erythrocytic differentiation,” Blood, vol. 112, no. 3, pp. 576–584, 2008.
[147]
O. Klimchenko, M. Mori, A. DiStefano et al., “A common bipotent progenitor generates the erythroid and megakaryocyte lineages in embryonic stem cell-derived primitive hematopoiesis,” Blood, vol. 114, no. 8, pp. 1506–1517, 2009.
[148]
M. R. Tallack and A. C. Perkins, “Megakaryocyte-erythroid lineage promiscuity in EKLF null mouse blood,” Haematologica, vol. 95, no. 1, pp. 144–147, 2010.
[149]
S. Dutt, A. Narla, K. Lin, et al., “Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells,” Blood, vol. 117, no. 9, pp. 2567–2576, 2011.
[150]
M. Cazzola, “Myelodysplastic syndrome with isolated 5q deletion (5q- syndrome). A clonal stem cell disorder characterized by defective ribosome biogenesis,” Haematologica, vol. 93, no. 7, pp. 967–972, 2008.
[151]
J. L. Barlow, L. F. Drynan, N. L. Trim, W. N. Erber, A. J. Warren, and A. N. J. McKenzie, “New insights into 5q- syndrome as a ribosomopathy,” Cell Cycle, vol. 9, no. 21, pp. 4286–4293, 2010.
[152]
Y. Liu, S. E. Elf, Y. Miyata et al., “p53 regulates hematopoietic stem cell quiescence,” Cell Stem Cell, vol. 4, no. 1, pp. 37–48, 2009.
[153]
Y. Liu, S. E. Elf, T. Asai et al., “The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior,” Cell Cycle, vol. 8, no. 19, pp. 3120–3124, 2009.
[154]
E. Wattel, C. Preudhomme, B. Hecquet et al., “p53 Mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies,” Blood, vol. 84, no. 9, pp. 3148–3157, 1994.
[155]
Y. Kita-Sasai, S. Horiike, S. Misawa et al., “International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome,” British Journal of Haematology, vol. 115, no. 2, pp. 309–312, 2001.
[156]
S. Horiike, Y. Kita-Sasai, M. Nakao, and M. Taniwaki, “Configuration of the TP53 gene as an independent prognostic parameter of myelodysplastic syndrome,” Leukemia and Lymphoma, vol. 44, no. 6, pp. 915–922, 2003.
[157]
L. Garderet, L. Kobari, C. Mazurier et al., “Unimpaired terminal erythroid differentiation and preserved enucleation capacity in myelodysplastic 5q(del) clones: a single cell study,” Haematologica, vol. 95, no. 3, pp. 398–405, 2010.
[158]
T. M. A. Neildez-Nguyen, H. Wajcman, M. C. Marden et al., “Human erythroid cells produced ex vivo at large scale differentiate into red blood cells in vivo,” Nature Biotechnology, vol. 20, no. 5, pp. 467–472, 2002.
[159]
M. C. Giarratana, L. Kobari, H. Lapillonne et al., “Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells,” Nature Biotechnology, vol. 23, no. 1, pp. 69–74, 2005.
[160]
M. J？dersten, “Pathophysiology and treatment of the myelodysplastic syndrome with isolated 5q deletion,” Haematologica, vol. 95, no. 3, pp. 348–351, 2010.
[161]
M. Virgilio, E. Payne, A. Narla, et al., “Treatment of zebrafish models of ribosomopathies (Diamond Blackfan anemia (DBA) and 5q-syndrome with Lleucine results in an improvement of anemia and development defects: evidence for a common pathway,” Blood, vol. 116, abstract 195, pp. 89–90, 2010.
[162]
J. Cmejlova, L. Dolezalova, D. Pospisilova, K. Petrtylova, J. Petrak, and R. Cmejla, “Translational efficiency in patients with Diamond-Blackfan anemia,” Haematologica, vol. 91, no. 11, pp. 1456–1464, 2006.
[163]
J. C. Anthony, T. G. Anthony, S. R. Kimball, T. C. Vary, and L. S. Jefferson, “Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased elF4F formation,” Journal of Nutrition, vol. 130, no. 2, pp. 139–145, 2000.
[164]
C. J. Lynch, B. J. Patson, J. Anthony, et al., “Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue,” American Journal of Physiology, vol. 283, pp. E506–E513, 2002.
[165]
L. E. Norton and D. K. Layman, “Leucine regulates translation initiation of protein synthesis in skeletal muscle after excercise,” Journal of Nutrition, vol. 136, pp. 533S–537S, 2006.
[166]
J. Escobar, J. W. Frank, A. Suryawan, et al., “Amino acid availability and age affect the leucine stimulation of protein synthesis and eIF4F formation in muscle,” American Journal of Physiology, vol. 293, pp. E1615–E1621, 2007.
[167]
D. Pospisilova, J. Cmejlova, J. Hak, T. Adam, and R. Cmejla, “Successful treatment of a Diamond-Blackfan anemia patient with amino acid leucine,” Haematologica, vol. 92, no. 5, pp. e66–67, 2007.
[168]
A. List, G. Dewald, J. Bennett et al., “Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion,” The New England Journal of Medicine, vol. 355, no. 14, pp. 1456–1465, 2006.
[169]
M. Melchert, V. Kale, and A. List, “The role of lenalidomide in the treatment of patients with chromosome 5q deletion and other myelodysplastic syndromes,” Current Opinion in Hematology, vol. 14, no. 2, pp. 123–129, 2007.
[170]
A. F. List, “Lenalidomide—the phoenix rises,” The New England Journal of Medicine, vol. 357, no. 21, pp. 2183–2186, 2007.
[171]
S. Kurtin and A. List, “Durable long-term responses in patients with myelodysplastic syndromes treated with lenalidomide,” Clinical Lymphoma and Myeloma, vol. 9, no. 3, pp. E10–E13, 2009.
[172]
R. S. Komrojki and A. F. List, “Lenalidomide for teatment of myelodysplastic syndromes: current status and future directions,” Hematology/Oncology Clinics of North America, vol. 24, pp. 377–388, 2010.
[173]
S. M. Post and A. Quintás-Cardama, “Closing in on the pathogenesis of the 5q- syndrome,” Expert Review of Anticancer Therapy, vol. 10, no. 5, pp. 655–658, 2010.
[174]
A. Raza, J. A. Reeves, E. J. Feldman et al., “Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q,” Blood, vol. 111, no. 1, pp. 86–93, 2008.
[175]
B. L. Ebert, N. Galili, P. Tamayo et al., “An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome,” PLoS Medicine, vol. 5, no. 2, pp. 0312–0322, 2008.
[176]
C. Chen, D. T. Bowen, A. A. N. Giagounidis, B. Schlegelberger, S. Haase, and E. G. Wright, “Identification of disease- and therapy-associated proteome changes in the sera of patients with myelodysplastic syndromes and del(5q),” Leukemia, vol. 24, no. 11, pp. 1875–1884, 2010.
[177]
S. Wei, X. Chen, K. Rocha et al., “A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 31, pp. 12974–12979, 2009.
[178]
S. H. Kimura and H. Nojima, “Cyclin G1 associates with MDM2 and regulates accumulation and degradation of p53 protein,” Genes to Cells, vol. 7, no. 8, pp. 869–880, 2002.
[179]
X. K. Zhang and D. K. Watson, “The FLI-1 transcription factor is a short-lived phosphoprotein in T cells,” Journal of Biochemistry, vol. 137, no. 3, pp. 297–302, 2005.
[180]
J. B. Bartlett, K. Dredge, and A. G. Dalgleish, “The evolution of thalidomide and its IMiD derivatives as anticancer agents,” Nature Reviews Cancer, vol. 4, no. 4, pp. 314–322, 2004.
[181]
A. Pellagatti, M. J？dersten, A. M. Forsblom et al., “Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 27, pp. 11406–11411, 2007.
[182]
E. N. Oliva, M. Cuzzola, F. Nobile et al., “Changes in RPS14 expression levels during lenalidomide treatment in Low- and Intermediate-1-risk myelodysplastic syndromes with chromosome 5q deletion,” European Journal of Haematology, vol. 85, no. 3, pp. 231–235, 2010.
[183]
C. P. Venner, A. F. List, T. J. Nevill, et al., “Induction of micro RNA-143 and 145 in pre-treatment CD34+ cells from patients with myelodysplastic syndrome (MDS) after in vitro exposure to lenalidomide correlates with clinical response in patients harboring the del5q abnormality,” Blood, vol. 116, abstract 123, p. 60, 2010.
[184]
M. Ximeri, A. Galanopoulos, M. Klaus et al., “Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion,” Haematologica, vol. 95, no. 3, pp. 406–414, 2010.
[185]
R. Tehranchi, P. S. Woll, K. Anderson et al., “Persistent malignant stem cells in del(5q) myelodysplasia in remission,” The New England Journal of Medicine, vol. 363, no. 11, pp. 1025–1037, 2010.
