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.

Institute of Hematology and Blood Transfusion U Nemocnice 1 128 20 Prague 2 Czech Republic ; Center of Experimental Hematology 1st Medical Faculty Charles University Institute of Pathological Physiology 128 53 Prague 2 Czech Republic

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Haase D, Germing U, Schanz J, 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. 2007;110(13):4385–4395. PubMed

Hasserjian RP, Le Beau MM, List AF, et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer Press; 2007.

Van Den Berghe H, Cassiman JJ, David G. Distinct haematological disorder with deletion of long arm of No. 5 chromosome. Nature. 1974;251(5474):437–438. PubMed

Van Den Berghe H, Vermaelen K, Mecucci C. The 5q- anomaly. Cancer Genetics and Cytogenetics. 1985;17(3):189–255. PubMed

Nimer SD, Golde DW. The 5q-abnormality. Blood. 1987;70(6):1705–1712. PubMed

Mathew P, Tefferi A, Dewald GW, et al. The 5q- syndrome: a single-institution study of 43 consecutive patients. Blood. 1993;81(4):1040–1045. PubMed

Boultwood J, Lewis S, Wainscoat JS. The 5q- syndrome. Blood. 1994;84(10):3253–3260. PubMed

Van Den Berghe H, Michaux L. 5q-, twenty-five years later: a synopsis. Cancer Genetics and Cytogenetics. 1997;94(1):1–7. PubMed

Giagounidis AAN, Germing U, Wainscoat JS, Boultwood J, Aul C. The 5q-syndrome. Hematology. 2004;9(4):271–277. PubMed

Mohamedali A, Mufti GJ. Van-den Berghe’s 5q- syndrome in 2008. British Journal of Haematology. 2009;144(2):157–168. PubMed

Willman CL, Sever CE, Pallavicini MG, et al. Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemic myelodysplasia. Science. 1993;259(5097):968–971. PubMed

Boultwood J, Fidler C, Lewis S, 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. 1993;82(9):2611–2616. PubMed

Le Beau MM, Espinosa R, Neuman WL, 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. 1993;90(12):5484–5488. PubMed PMC

Boultwood J, Fidler C, Lewis S, 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. 1994;19(3):425–432. PubMed

Boultwood J, Fidler C, Strickson AJ, et al. Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome. Blood. 2002;99(12):4638–4641. PubMed

Jaju RJ, Boultwood J, Oliveret FJ, et al. Molecular cytogenc definition of the critical deleted region in the 5q- syndrome. Genes Chromosomes Cancer. 1998;22:251–256. PubMed

Zhao N, Stoffel A, Wang PW, 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. 1997;94(13):6948–6953. PubMed PMC

Heaney ML, Golde DW. Myelodysplasia. The New England Journal of Medicine. 1999;340(21):1649–1660. PubMed

Nilsson L, Astrand-Grundstrom I, Arvidsson I, 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. 2000;96(6):2012–2021. PubMed

Eisenmann KM, Dykema KJ, Matheson SF, et al. 5q- myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics. Oncogene. 2009;28(39):3429–3441. PubMed

Boultwood J, Pellagatti A, Cattan H, et al. Gene expression profiling of CD34+ cells in patients with the 5q- syndrome. British Journal of Haematology. 2007;139(4):578–589. PubMed

Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America. 1971;68(4):820–823. PubMed PMC

Paige AJW. Redefining tumour suppressor genes: exceptions to the two-hit hypothesis. Cellular and Molecular Life Sciences. 2003;60(10):2147–2163. PubMed PMC

Ebert BL. Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer. Leukemia. 2009;23(7):1252–1256. PubMed

Narla A, Ebert BL. Ribosomopathies: human disorders of ribosome dysfunction. Blood. 2010;115(16):3196–3205. PubMed PMC

Tormo M, Marugán I, Calabuig M. Myelodysplastic syndromes: an update on molecular pathology. Clinical and Translational Oncology. 2010;12(10):652–661. PubMed

Davids MS, Steensma DP. The molecular pathogenesis of myelodysplastic syndromes. Cancer Biology and Therapy. 2010;10(4):309–319. PubMed

Berger AH, Pandolfi PP. Haplo-insufficiency: a driving force in cancer. Journal of Pathology. 2011;223(2):137–146. PubMed

Montaville P, Dai Y, Cheung CY, et al. Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22. Biochimica et Biophysica Acta. 2006;1763(11):1335–1343. PubMed

Jia J, Tong C, Wang B, Luo L, Jiang J. Hedgehog signalling activity of smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature. 2004;432(7020):1045–1050. PubMed

Hämmerlein A, Weiske J, Huber O. 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. 2005;62(5):606–618. PubMed PMC

Lehmann S, O’Kelly J, Raynaud S, Funk SE, Sage EH, Koeffler HP. Common deleted genes in the 5q-syndrome: thrombocytopenia and reduced erythroid colony formation in SPARC null mice. Leukemia. 2007;21(9):1931–1936. PubMed

Ebert BL, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature. 2008;451(7176):335–339. PubMed PMC

Ellis SR, Gleizes PE. Diamond Blackfan anemia: ribosomal proteins going rogue. Seminars in Hematology. 2011;48:89–96. PubMed

Valencia A, Cervera J, Such E, Sanz MA, Sanz GF. Lack of RPS14 promoter aberrant methylation supports the haploinsufficiency model for the 5q- Syndrome. Blood. 2008;112(3):p. 918. PubMed

Draptchinskaia N, Gustavsson P, Andersson B, et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nature Genetics. 1999;21(2):169–175. PubMed

Gazda HT, Grabowska A, Merida-Long LB, et al. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. American Journal of Human Genetics. 2006;79(6):1110–1118. PubMed PMC

Ganapathi KA, Shimamura A. Ribosomal dysfunction and inherited marrow failure. British Journal of Haematology. 2008;141(3):376–387. PubMed

Campagnoli MF, Ramenghi U, Armiraglio M, et al. RPS19 mutations in patients with Diamond-Blackfan anemia. Human Mutation. 2008;29(7):911–920. PubMed

Cmejla R, Cmejlova J, Handrkova H, 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. 2009;30(3):321–327. PubMed

Lipton JM, Ellis SR. Diamond-blackfan anemia: diagnosis, treatment, and molecular pathogenesis. Hematology/Oncology Clinics of North America. 2009;23(2):261–282. PubMed PMC

Doherty L, Sheen MR, Vlachos A, et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in diamond-blackfan anemia. American Journal of Human Genetics. 2010;86(2):222–228. PubMed PMC

Devlin EE, DaCosta L, Mohandas N, Elliott G, Bodine DM. A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia. Blood. 2010;116(15):2826–2835. PubMed PMC

Hoefele J, Bertrand AM, Stehr M, et al. Disorders of sex development and Diamond-Blackfan anemia: is there an association? Pediatric Nephrology. 2010;25(7):1255–1261. PubMed

Ito E, Konno Y, Toki T, Terui K. Molecular pathogenesis in Diamond-Blackfan anemia. International Journal of Hematology. 2010;92(3):413–418. PubMed

Boria I, Garelli E, Gazda HT, et al. The ribosomal basis of diamond-blackfan anemia: mutation and database update. Human Mutation. 2010;31(12):1269–1279. PubMed PMC

Josephs HW. Anemia of infancy and early childhood. Medicine. 1936;15:307–451.

Diamond LK, Blackfan KD. Hypoplastic anemia. Am. J. Dis. Child. 1938;56:464–467.

Barlow JL, Drynan LF, Hewett DR, et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome. Nature Medicine. 2010;16(1):59–66. PubMed PMC

Pellagatti A, Hellström-Lindberg E, Giagounidis A, et al. Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes. British Journal of Haematology. 2008;142(1):57–64. PubMed PMC

Gazda HT, Kho AT, Sanoudou D, et al. Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia. Stem Cells. 2006;24(9):2034–2044. PubMed PMC

Sridhar K, Ross DT, Tibshirani R, Butte AJ, Greenberg PL. Relationship of differential gene expression profiles in CD34+ myelodysplastic syndrome marrow cells to disease subtype and progression. Blood. 2009;114(23):4847–4858. PubMed PMC

He H, Sun Y. Ribosomal protein S27L is a direct p53 target that regulates apoptosis. Oncogene. 2007;26(19):2707–2716. PubMed

Li J, Tan J, Zhuang L, et al. Ribosomal protein S27-like, a p53-inducible modulator of cell fate in response to genotoxic stress. Cancer Research. 2007;67(23):11317–11326. PubMed

Farquhar MJ, Bowen DT. Oxidative stress and the myelodysplastic syndromes. International Journal of Hematology. 2003;77(4):342–350. PubMed

Ghoti H, Amer J, Winder A, Rachmilewitz E, Fibach E. Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome. European Journal of Haematology. 2007;79(6):463–467. PubMed

Novotna B, Bagryantseva Y, Siskova M, Neuwirtova R. Oxidative DNA damage in bone marrow cells of patients with low-risk myelodysplastic syndrome. Leukemia Research. 2009;33(2):340–343. PubMed

Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–233. PubMed PMC

Starczynowski DT, Kuchenbauer F, Argiropoulos B, et al. Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype. Nature Medicine. 2010;16(1):49–58. PubMed

Terpos E, Verrou E, Banti A, Kaloutsi V, Lazaridou A, Zervas K. Bortezomib is an effective agent for MDS/MPD syndrome with 5q- anomaly and thrombocytosis. Leukemia Research. 2007;31(4):559–562. PubMed

Starczynowski DT, Morin R, McPherson A, et al. Genome-wide identification of human microRNAs located in leukemia-associated genomic alterations. Blood. 2011;117:595–607. PubMed

Kumar M, Narla A, Nonami A, et al. Coordinate 1oss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome. Blood. 2011;118:4663–4673. PubMed PMC

Boultwood J, Pellagatti A, McKenzie ANJ, Wainscoat JS. Advances in the 5q-syndrome. Blood. 2010;116(26):5803–5811. PubMed

Votavova H, Grmanova M, Dostalova Merkerova M, et al. Differential expression of microRNAs in CD34+ cells of 5q- syndrome. Journal of Hematology and Oncology. 2011;4:p. 1. PubMed PMC

Suzuki HI, Yamagata K, Sugimoto K, Iwamoto T, Kato S, Miyazono K. Modulation of microRNA processing by p53. Nature. 2009;460(7254):529–533. PubMed

Boominathan L. The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network. Cancer and Metastasis Reviews. 2010;29(4):613–639. PubMed

Ozen M, Creighton CJ, Ozdemir M, Ittmann M. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008;27(12):1788–1793. PubMed

Wang Y, Lee CGL. MicroRNA and cancer—focus on apoptosis. Journal of Cellular and Molecular Medicine. 2009;13(1):12–23. PubMed PMC

Akao Y, Nakagawa Y, Naoe T. MicroRNA-143 and -145 in colon cancer. DNA and Cell Biology. 2007;26(5):311–320. PubMed

Sachdeva M, Mo YY. miR-145-mediated suppression of cell growth, invasion and metastasis. American Journal of Translational Research. 2010;2(2):170–180. PubMed PMC

Zhang J, Guo H, Zhang H, et al. Putative tumor suppressor miR-145 inhibits colon cancer cell growth by targeting oncogene friend leukemia virus integration 1 gene. Cancer. 2011;117(1):86–95. PubMed PMC

Shi B, Sepp-Lorenzino L, Prisco M, Linsley P, Deangelis T, Baserga R. Micro RNA 145 targets the insulin receptor substrate-1 and inhibits the growth of colon cancer cells. Journal of Biological Chemistry. 2007;282(45):32582–32590. PubMed

Zhang J, Guo H, Qian G, et al. MiR-145, a new regulator of the DNA Fragmentation Factor-45 (DFF45)-mediated apoptotic network. Molecular Cancer. 2010;9, article 211 PubMed PMC

Chiu CC, Lin CHMY, Fang K. Etoposide (VP-16) sensitizes p53-deficient human non-small cell lung cancer cells to caspase-7-mediated apoptosis. Apoptosis. 2005;10(3):643–650. PubMed

Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997;89(2):175–184. PubMed

Williams AE, Perry MM, Moschos SA, Larner-Svensson HM, Lindsay MA. Role of miRNA-146a in the regulation of the innate immune response and cancer. Biochemical Society Transactions. 2008;36(6):1211–1215. PubMed

Li L, Chen X-P, Li Y-J. MicroRNA-146a and human disease. Scandinavian Journal of Immunology. 2010;71:227–231. PubMed

Starczynowski DT, Kuchenbauer F, Wegrzyn J. MicroRNA-146a disrupts hematopoietic differentiation and survival. Experimental Hematology. 2011;39:167–178. PubMed

Cordes KR, Sheehy NT, White MP, et al. MiR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009;460(7256):705–710. PubMed PMC

Boettger T, Beetz N, Kostin S, et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. Journal of Clinical Investigation. 2009;119(9):2634–2647. PubMed PMC

Dostalova Merkerova M, Krejcik Z, Votavova H, Belickova M, Vasikova A, Cermak J. Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome. European Journal of Human Genetics. 2011;19:313–319. PubMed PMC

Panić L, Montagne J, Cokarić M, Volarević S. S6-haploinsufficiency activates the p53 tumor suppressor. Cell Cycle. 2007;6(1):20–24. PubMed

Danilova N, Sakamoto KM, Lin S. Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family. Blood. 2008;112(13):5228–5237. PubMed

Jones NC, Lynn ML, Gaudenz K, et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nature Medicine. 2008;14(2):125–133. PubMed PMC

McGowan KA, Li JZ, Park CY, et al. Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects. Nature Genetics. 2008;40(8):963–970. PubMed PMC

Barkić M, Crnomarković S, Grabušić K, et al. The p53 tumor suppressor causes congenital malformations in Rpl24-deficient mice and promotes their survival. Molecular and Cellular Biology. 2009;29(10):2489–2504. PubMed PMC

Constantinou C, Elia A, Clemens MJ. Activation of p53 stimulates proteasome-dependent truncation of elF4E-binding protein 1 (4E-BP1) Biology of the Cell. 2008;100(5):279–289. PubMed

Momand J, Wu HH, Dasgupta G. MDM2-master regulator of the p53 tumor suppressor protein. Gene. 2000;242(1-2):15–29. PubMed

Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. Journal of Biological Chemistry. 2000;275(12):8945–8951. PubMed

Clegg HV, Itahana K, Zhang Y. Unlocking the Mdm2-p53 loop: ubiquitin is the key. Cell Cycle. 2008;7(3):287–292. PubMed

Dai MS, Lu H. Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. Journal of Biological Chemistry. 2004;279(43):44475–44482. PubMed

Lohrum MAE, Ludwig RL, Kubbutat MHG, Hanlon M, Vousden KH. Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell. 2003;3(6):577–587. PubMed

Zhang Y, Wolf GW, Bhat K, et al. Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway. Molecular and Cellular Biology. 2003;23(23):8902–8912. PubMed PMC

Bhat KP, Itahana K, Jin A, Zhang Y. Essential role of ribosomal protein L11 in mediating growth inhibition-induced p53 activation. EMBO Journal. 2004;23(12):2402–2412. PubMed PMC

Dai MS, Zeng SX, Jin Y, Sun XX, David L, Lu H. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Molecular and Cellular Biology. 2004;24(17):7654–7668. PubMed PMC

Ofir-Rosenfeld Y, Boggs K, Michael D, Kastan MB, Oren M. Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26. Molecular Cell. 2008;32(2):180–189. PubMed PMC

Chen D, Zhang Z, Li M, 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. 2007;26(35):5029–5037. PubMed

Zhang Y, Lu H. Signaling to p53: ribosomal proteins find their way. Cancer Cell. 2009;16(5):369–377. PubMed PMC

Zhang Y, Wang J, Yuan Y, et al. Negative regulation of HDM2 to attenuate p53 degradation by ribosomal protein L26. Nucleic Acids Research. 2010;38(19):6544–6554. Article ID gkq536. PubMed PMC

Pestov DG, Strezoska Z, Lau LF. 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. 2001;21(13):4246–4255. PubMed PMC

Deisenroth C, Zhang Y. Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway. Oncogene. 2010;29(30):4253–4260. PubMed

Gilkes DM, Chen L, Chen J. MDMX regulation of p53 response to ribosomal stress. EMBO Journal. 2006;25(23):5614–5625. PubMed PMC

Sun XX, Wang YG, Xirodimas DP, Dai MS. Perturbation of 60 S ribosomal biogenesis results in ribosomal protein L5- and L11-dependent p53 activation. Journal of Biological Chemistry. 2010;285(33):25812–25821. PubMed PMC

Pellagatti A, Marafioti T, Paterson JC, et al. Induction of p53 and up-regulation of the p53 pathway in the human 5q- syndrome. Blood. 2010;115(13):2721–2723. PubMed

Perry ME. The regulation of the p53-mediated stress response by MDM2 and MDM4. Cold Spring Harbor Perspectives in Biology. 2010;2(1, article a000968) PubMed PMC

Ho JSL, Ma W, Mao DYL, Benchimol S. p53-dependent transcriptional repression of c-myc is required for G 1 cell cycle arrest. Molecular and Cellular Biology. 2005;25(17):7423–7431. PubMed PMC

Sachdeva M, Zhu S, Wu F, 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. 2009;106(9):3207–3212. PubMed PMC

Sachdeva M, Mo YY. p53 and c-myc: how does the cell balance "yin" and "yang"? Cell Cycle. 2009;8(9):p. 1303. PubMed

Truong AHL, Cervi D, Lee J, Ben-David Y. Direct transcriptional regulation of MDM2 by Fli-1. Oncogene. 2005;24(6):962–969. PubMed

Christiansen DH, Andersen MK, Pedersen-Bjergaard J. 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. 2001;19(5):1405–1413. PubMed

Pedersen-Bjergaard J, Andersen MK, Andersen MT, Christiansen DH. Genetics of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2008;22(2):240–248. PubMed

Jädersten M, Saft L, Pellagatti A, et al. Clonal heterogeneity in the 5q- syndrome: P53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Haematologica. 2009;94(12):1762–1766. PubMed PMC

Jädersten M, Saft L, Smith A, et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict dinase progression. Journal of Clinical Oncology. 2011;29:1971–1979. PubMed

Lim CM, Cater MA, Mercer JFB, La Fontaine S. Copper-dependent interaction of dynactin subunit p62 with the N terminus of ATP7B but not ATP7A. Journal of Biological Chemistry. 2006;281(20):14006–14014. PubMed

Patel SR, Richardson JL, Schulze H, et al. Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes. Blood. 2005;106(13):4076–4085. PubMed PMC

Italiano JE, Jr., Patel-Hett S, Hartwig JH. Mechanics of proplatelet elaboration. Journal of Thrombosis and Haemostasis. 2007;5, supplement 1:18–23. PubMed

He F, Wang CT, Gou LT. RNA-binding motif protein RBM22 is required for normal development of zebrafish embryos. Genetics and Molecular Research. 2009;8(4):1466–1473. PubMed

Grisendi S, Bernardi R, Rossi M, et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature. 2005;437(7055):147–153. PubMed

Grisendi S, Mecucci C, Falini B, Pandolfi PP. Nucleophosmin and cancer. Nature Reviews Cancer. 2006;6(7):493–505. PubMed

Sportoletti P, Grisendi S, Majid SM, et al. Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood. 2008;111(7):3859–3862. PubMed PMC

Cazzaniga G, Dell’Oro MG, Mecucci C, et al. Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype. Blood. 2005;106(4):1419–1422. PubMed

Rau R, Brown P. Nucleophosmin (NPM1) mutations in adult and childhood acute myeloid leukaemia: towards definition of a new leukaemia entity. Hematological Oncology. 2009;27(4):171–181. PubMed PMC

Walter MJ. Del(5q): gene dosage matters. Blood. 2007;110(2):473–474.

Neuwirtova R, Fuchs O, Provaznikova D, et al. Fli-1 and EKLF gene expression in patients with MDS 5q- syndrome. Blood. 2009;114:1090–1091. abstract no. 2788, Proceedings of the 51st Annual Meeting of the American Society of Hematology, December 5–8, 2009, New Orleans, La, USA.

Neuwirtova R, Fuchs O, Jonasova A, 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.

Ben-David Y, Giddens EB, Letwin K, Bernstein A. 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. 1991;5(6):908–918. PubMed

Watson DK, Smyth FE, Thompson DM, 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. 1992;3(10):705–713. PubMed

Prasad DDK, Rao VN, Reddy ESP. Structure and expression of human Fli-1 gene. Cancer Research. 1992;52(20):5833–5837. PubMed

Selleri L, Giovannini M, Romo A, 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. 1994;67(2):129–136. PubMed

Starck J, Cohet N, Gonnet C, et al. Functional cross-antagonism between transcription factors FLI-1 and EKLF. Molecular and Cellular Biology. 2003;23(4):1390–1402. PubMed PMC

Eisbacher M, Holmes ML, Newton A, 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. 2003;23(10):3427–3441. PubMed PMC

Jackers P, Szalai G, Moussa O, Watson DK. Ets-dependent regulation of target gene expression during megakaryopoiesis. Journal of Biological Chemistry. 2004;279(50):52183–52190. PubMed

Svenson JL, Chike-Harris K, Amria MY, Nowling TK. The mouse and human Fli1 genes are similarly regulated by Ets factors in T cells. Genes and Immunity. 2010;11(2):161–172. PubMed PMC

Starck J, Doubeikovski A, Sarrazin S, 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. 1999;19(1):121–135. PubMed PMC

Rekhtman N, Radparvar F, Evans T, Skoultchi AI. Direct interaction of hematopoietic transcription factors PU.1 and GATA- 1: functional antagonism in erythroid cells. Genes and Development. 1999;13(11):1398–1411. PubMed PMC

Zhang P, Zhang X, Iwama A, et al. PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding. Blood. 2000;96(8):2641–2648. PubMed

Juban G, Giraud G, Guyot B, et al. Spi-1 and Fli-1 directly activate common target genes involved in ribosome biogenesis in friend erythroleukemic cells. Molecular and Cellular Biology. 2009;29(10):2852–2864. PubMed PMC

Starczynowski DT, Karsan A. Innate immune signaling in the myelodysplastic syndromes. Hematology/Oncology Clinics of North America. 2010;24:343–359. PubMed

Hodge DR, Xiao W, Clausen PA, Heidecker G, Szyf M, Farrar WL. Interleukin-6 regulation of the human DNA methyltransferase (HDNMT) gene in human erythroleukemia cells. Journal of Biological Chemistry. 2001;276(43):39508–39511. PubMed

Hodge DR, Li D, Qi SM, Farrar WL. IL-6 induces expression of the Fli-1 proto-oncogene via STAT3. Biochemical and Biophysical Research Communications. 2002;292:287–291. PubMed

Tallack MR, Whitington T, Yuen WS, et al. A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells. Genome Research. 2010;20(8):1052–1063. PubMed PMC

Siatecka M, Bieker JJ. The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood. 2011;118:2044–2054. PubMed PMC

Doré LC, Crispino JD. Transcription factor in erythroid cell and megakaryocyte development. Blood. 2011;118:231–239. PubMed PMC

Borg J, Papadopoulos P, Georgitsi M, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nature Genetics. 2010;42(9):801–805. PubMed PMC

Frontelo P, Manwani D, Galdass M, et al. Novel role for EKLF in megakaryocyte lineage commitment. Blood. 2007;110(12):3871–3880. PubMed PMC

Bouilloux F, Juban G, Cohet N, et al. EKLF restricts megakaryocytic differentiation at the benefit of erythrocytic differentiation. Blood. 2008;112(3):576–584. PubMed

Klimchenko O, Mori M, DiStefano A, et al. A common bipotent progenitor generates the erythroid and megakaryocyte lineages in embryonic stem cell-derived primitive hematopoiesis. Blood. 2009;114(8):1506–1517. PubMed

Tallack MR, Perkins AC. Megakaryocyte-erythroid lineage promiscuity in EKLF null mouse blood. Haematologica. 2010;95(1):144–147. PubMed PMC

Dutt S, Narla A, Lin K, et al. Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood. 2011;117(9):2567–2576. PubMed PMC

Cazzola M. Myelodysplastic syndrome with isolated 5q deletion (5q- syndrome). A clonal stem cell disorder characterized by defective ribosome biogenesis. Haematologica. 2008;93(7):967–972. PubMed

Barlow JL, Drynan LF, Trim NL, Erber WN, Warren AJ, McKenzie ANJ. New insights into 5q- syndrome as a ribosomopathy. Cell Cycle. 2010;9(21):4286–4293. PubMed

Liu Y, Elf SE, Miyata Y, et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell. 2009;4(1):37–48. PubMed PMC

Liu Y, Elf SE, Asai T, et al. The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior. Cell Cycle. 2009;8(19):3120–3124. PubMed PMC

Wattel E, Preudhomme C, Hecquet B, et al. p53 Mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood. 1994;84(9):3148–3157. PubMed

Kita-Sasai Y, Horiike S, Misawa S, et al. International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome. British Journal of Haematology. 2001;115(2):309–312. PubMed

Horiike S, Kita-Sasai Y, Nakao M, Taniwaki M. Configuration of the TP53 gene as an independent prognostic parameter of myelodysplastic syndrome. Leukemia and Lymphoma. 2003;44(6):915–922. PubMed

Garderet L, Kobari L, Mazurier C, et al. Unimpaired terminal erythroid differentiation and preserved enucleation capacity in myelodysplastic 5q(del) clones: a single cell study. Haematologica. 2010;95(3):398–405. PubMed PMC

Neildez-Nguyen TMA, Wajcman H, Marden MC, et al. Human erythroid cells produced ex vivo at large scale differentiate into red blood cells in vivo. Nature Biotechnology. 2002;20(5):467–472. PubMed

Giarratana MC, Kobari L, Lapillonne H, et al. Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells. Nature Biotechnology. 2005;23(1):69–74. PubMed

Jädersten M. Pathophysiology and treatment of the myelodysplastic syndrome with isolated 5q deletion. Haematologica. 2010;95(3):348–351. PubMed PMC

Virgilio M, Payne E, Narla A, 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. 2010;116, abstract 195:89–90.

Cmejlova J, Dolezalova L, Pospisilova D, Petrtylova K, Petrak J, Cmejla R. Translational efficiency in patients with Diamond-Blackfan anemia. Haematologica. 2006;91(11):1456–1464. PubMed

Anthony JC, Anthony TG, Kimball SR, Vary TC, Jefferson LS. Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased elF4F formation. Journal of Nutrition. 2000;130(2):139–145. PubMed

Lynch CJ, Patson BJ, Anthony J, et al. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. American Journal of Physiology. 2002;283:E506–E513. PubMed

Norton LE, Layman DK. Leucine regulates translation initiation of protein synthesis in skeletal muscle after excercise. Journal of Nutrition. 2006;136:533S–537S. PubMed

Escobar J, Frank JW, Suryawan A, et al. Amino acid availability and age affect the leucine stimulation of protein synthesis and eIF4F formation in muscle. American Journal of Physiology. 2007;293:E1615–E1621. PubMed PMC

Pospisilova D, Cmejlova J, Hak J, Adam T, Cmejla R. Successful treatment of a Diamond-Blackfan anemia patient with amino acid leucine. Haematologica. 2007;92(5):e66–67. PubMed

List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. The New England Journal of Medicine. 2006;355(14):1456–1465. PubMed

Melchert M, Kale V, List A. The role of lenalidomide in the treatment of patients with chromosome 5q deletion and other myelodysplastic syndromes. Current Opinion in Hematology. 2007;14(2):123–129. PubMed

List AF. Lenalidomide—the phoenix rises. The New England Journal of Medicine. 2007;357(21):2183–2186. PubMed

Kurtin S, List A. Durable long-term responses in patients with myelodysplastic syndromes treated with lenalidomide. Clinical Lymphoma and Myeloma. 2009;9(3):E10–E13. PubMed

Komrojki RS, List AF. Lenalidomide for teatment of myelodysplastic syndromes: current status and future directions. Hematology/Oncology Clinics of North America. 2010;24:377–388. PubMed

Post SM, Quintás-Cardama A. Closing in on the pathogenesis of the 5q- syndrome. Expert Review of Anticancer Therapy. 2010;10(5):655–658. PubMed

Raza A, Reeves JA, Feldman EJ, 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. 2008;111(1):86–93. PubMed

Ebert BL, Galili N, Tamayo P, et al. An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome. PLoS Medicine. 2008;5(2):0312–0322. PubMed PMC

Chen C, Bowen DT, Giagounidis AAN, Schlegelberger B, Haase S, Wright EG. Identification of disease- and therapy-associated proteome changes in the sera of patients with myelodysplastic syndromes and del(5q) Leukemia. 2010;24(11):1875–1884. PubMed

Wei S, Chen X, Rocha K, 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. 2009;106(31):12974–12979. PubMed PMC

Kimura SH, Nojima H. Cyclin G1 associates with MDM2 and regulates accumulation and degradation of p53 protein. Genes to Cells. 2002;7(8):869–880. PubMed

Zhang XK, Watson DK. The FLI-1 transcription factor is a short-lived phosphoprotein in T cells. Journal of Biochemistry. 2005;137(3):297–302. PubMed

Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nature Reviews Cancer. 2004;4(4):314–322. PubMed

Pellagatti A, Jädersten M, Forsblom AM, 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. 2007;104(27):11406–11411. PubMed PMC

Oliva EN, Cuzzola M, Nobile F, 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. 2010;85(3):231–235. PubMed

Venner CP, List AF, Nevill TJ, 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. 2010;116, abstract 123:p. 60.

Ximeri M, Galanopoulos A, Klaus M, et al. Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion. Haematologica. 2010;95(3):406–414. PubMed PMC

Tehranchi R, Woll PS, Anderson K, et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. The New England Journal of Medicine. 2010;363(11):1025–1037. PubMed