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Introductory Chapter: Progress in Myelodysplastic Syndrome Area

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Ota Fuchs

Published: 29 January 2019

DOI: 10.5772/intechopen.84594

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1. Advances in our knowledge of cytogenetic abnormalities andgene mutations

Myelodysplastic syndromes (MDS) constitute a group of age-associated heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis with peripheral cytopenias, dysplasia, and an increased risk of progression to acute myeloid leukemia (AML) [1, 2, 3, 4, 5, 6]. About 50% of cases of MDS are characterized by the presence of cytogenetic abnormalities. Losses of chromosomal material as del(5q), del(20q), monosomy 7 or del(7q), and del(Y) are most common cytogenetic abnormalities and are more frequent than gains of chromosomal material as trisomy 8 or trisomy 21 [7].

MDS are caused by abnormalities in many genes. The great progress in analysis of these mutations and in elucidation of relationships between gene mutations and clinical phenotypes of these disorders was achieved. Somatic mutations were found in more than 90%. Next-generation sequencing (NGS) detected about 10 different mutations in almost every patient with MDS. The majority of these mutations are nonpathogenic passenger mutations. However, one or more driver mutations in most patients with MDS are associated with the pathogenesis of MDS. Gene mutations affect proteins involved in various important cell processes as RNA-splicing, DNA methylation, histone and chromatin modifications, signal transduction, transcription (transcription factors), tumor suppressor (TP53), RAS pathway, and separation of sister chromatids during cell division (cohesion complex) [4, 8, 9, 10].

RNA-splicing and DNA methylation mutations occur early and are known as founding mutations. Other mutations are called subclonal mutations. No MDS-specific mutations exist. Strongly represented mutations in genes coding for proteins involved in DNA methylation, such as TET2, DNMT3A, and ASXL1, are common also in older individuals with normal blood count (clonal hematopoiesis of indeterminate potential/CHIP/) [11, 12]. Until now, mutations in TP53, EZH2, RUNX1, and SF3B1 predict independently overall survival (OS) of MDS patients. The first three mutations are associated with shorter OS but the last mutation is connected with better survival in refractory anemia with ring sideroblast (MDS-RS) and with thrombocytosis (RARS-T) [13, 14]. SF3B1 mutations are present in about 80% of MDS-RS and correlates with its development. SF3B1 mutations could alter the expression of the gene for ABCB7 transporter and abnormally regulate iron homeostasis in mitochondria mediating the phenotype of acquired MDS-RS [15]. Effects of other mutations are not clear up to now and results are often controversial.

We lack clinical methods to stop clonal development from relatively benign state of CHIP to malignancy. Especially, TP53-mutant clones induce progress to therapy-related MDS/AML. Therapy-related myeloid neoplasms have mutations in TP53 and epigenetic modifying genes, instead of mutations in tyrosine kinase and spliceosome genes [16]. The possible treatments are now the use of hypomethylating agents or in future anti-inflammatory therapy and clonally selective immunotherapies.

MDS are associated with genomic instability and extensive DNA damage caused by deficient repair mechanisms. Aberrations in DNA damage response/repair genes other than TP53 and some genes involved in DNA damage checkpoints are rare. Differential expression of homologous recombination DNA repair-associated genes during MDS progression was detected and could be confirmed as new biomarkers related to pathogenesis and poor prognosis in MDS [17, 18].


2. Advance in our understanding of del(5q) myelodysplastic syndrome pathogenesis and its treatment with lenalidomide

The greatest progress was achieved in the study of molecular pathogenesis of del(5q) MDS disease phenotype and its treatment by immunomodulatory or cereblon-binding drug lenalidomide [2, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35]. Ebert et al. described that impaired ribosome biosynthesis due to RPS14 (ribosomal protein 14 of the small ribosome subunit) gene haploinsufficiency leads to the E3 ubiquitin ligase HDM2 (human homolog to mouse double minute 2, major negative regulator of p53) inactivation by free ribosomal proteins, particularly RPL11 [36]. HDM2 degradation drives p53-mediated apoptosis of erythroid cells carrying the del(5q) aberration. This p53-mediated apoptosis of erythroid cells is a key effector of hypoplastic anemia in MDS patients with del(5q) [36]. RPS14 haploinsufficiency causes a block in erythroid differentiation mediated by calprotectin (the heterodimeric S100 calcium-binding proteins S100A8 and S100A9) [37]. Proinflammatory proteins, S100A9 and tumor necrosis factor-α, suppress the effect of erythropoietin in MDS [38]. Some patients originally considered as MDS patients without del(5q) can have a phenotype of atypical 5q− syndrome and can be sensitive to lenalidomide therapy because they have diminutive somatic deletions in the 5q region. These deletions were not identified by fluorescence in situ hybridization or cytogenetic testing but by single nucleotide polymorphism array genotyping [39]. Low RPS14 expression in 50–70% MDS patients without del(5q) confers higher apoptosis rate of nucleated erythrocytes and predicts prolonged survival [40, 41].

What is the mechanism of lenalidomide in del(5q) MDS based on what has been achieved and elucidated to date? Lenalidomide stabilizes E3 ubiquitin ligase HDM2, thereby accelerating p53 degradation [42, 43]. Lenalidomide inhibits phosphatases PP2a and Cdc25c (coregulators of cell cycle which genes are very commonly deleted in del(5q) MDS) with consequent G2 arrest of del(5q) MDS progenitors and their apoptosis. PP2a and Cdc25c inhibition by lenalidomide suppress HDM2 autoubiquitination and subsequent degradation. Thus, lenalidomide has been shown to not only reverse apoptosis within the erythroid compartment, but also directly induce apoptosis of the myeloid clone in del(5q) MDS [44, 45]. Lenalidomide upregulates expression of other two haploinsufficient genes located on chromosome 5q, genes for microRNAs (miR-145 and miR-146a) [46]. These miRs are involved in Toll-like receptor pathway, IL-6 induction, and regulation of megakaryopoiesis [20].

Ito et al. discovered that thalidomide (founding member of immunomodulatory drugs/IMiDs/) binds cereblon (CRBN) in the terminal C-region (parts of exons 10 and 11 of the CRBN gene code this IMiD binding region) [47]. Several researchers confirmed CRBN as target of lenalidomide in multiple myeloma (MM), lymphoma, chronic lymphocytic leukemia, and del(5q) MDS [48]. CRBN is the ubiquitously expressed 51 kDa protein with a putative role in cerebral development, especially memory and learning [49, 50].

Our group found that del(5q) MDS patients (the so-called 5q minus syndrome) have higher levels of full-length CRBN mRNA than other patients with lower risk MDS, linking higher levels of a known lenalidomide target CRBN and del(5q) MDS subgroup known to be especially sensitive to lenalidomide [51].

CRBN is a member and substrate receptor of the cullin 4 RING E3 ubiquitin ligase complex (CRL4). CRBN recruits substrate proteins to the CRL4 complex for ubiquitination and the subsequent degradation in proteasomes. IMiDs binds to CRBN in CRL4 complex and block normal endogenous substrates (CRBN and the homeobox transcription factor MEIS2 in multiple myeloma/MM/) from binding to CRL4 for ubiquitination and degradation [52]. After IMID binding to CRBN, CRL4 complex is recruiting transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) for ubiquitination and degradation in MM cells [53]. Degradation of these transcription factors explains lenalidomide’s growth inhibition of MM cells and increased interleukin-2 (IL-2) release from T cells. However, it is unlikely that degradation of IKZF1 and IKZF3 accounts for lenalidomide’s activity in MDS with del(5q). Fink et al. identified a novel target casein kinase1A1 (CSNK1A1) by quantitative proteomics in the myeloid cell line KG-1 [54]. CSNK1A1 is encoded in the del(5q) commonly deleted region and the gene is haploinsufficient. Lenalidomide treatment leads to increased ubiquitination of the remaining CSNK1A1 and decreased protein abundance. CSNK1A1 negatively regulates β-catenin which drives stem cell self-renewal, and CSNK1A1 haploinsufficiency causes the initial clonal expansion in patients with the del(5q) MDS and contributes to the pathogenesis of del(5q) MDS. The further inhibition of CSNK1A1 in del(5q) MDS is associated with del(5q) failure and p53 activation. The inhibition of CSNK1A1 reduced RPS6 phosphorylation, induced p53 expression and growth inhibition, and triggered myeloid differentiation program. TP53-null leukemia did not respond to CSNK1A1 inhibition, strongly supporting the importance of the p53 expression for the yield of CSNK1A1 inhibition. CSNK1A1 mutations have been recently found in 5–18% of MDS patients with del(5q) [55]. These mutations are associated similarly to the effect of TP53 mutations with rise to a poor prognosis in del(5q) MDS [56]. Other studies did not find impact of CSNK1A1 mutations on lenalidomide treatment in del(5q) MDS [57, 58].

Even if the treatment of del(5q) MDS patients with lenalidomide is very efficient, 50% of treated patients relapse after 2–3 years. Martinez-Hoyer et al. found that low platelet count and occurrence of additional mutations, mainly TP53 mutations induce lenalidomide resistance [59, 60, 61]. They used whole genome sequencing and observed in several resistant patients mutations in RUNX1 gene or decreased amount of RUNX1 transcript without aberration in TP53 [59]. Results were verified in model system of two human del(5q) lines, MDS-L and KG-1a. RUNX1 knock-out or RUNX1 shRNA increased proliferation and reduced apoptosis in lenalidomide-treated cells with decreased RUNX1 transcript. Therefore, effect of lenalidomide in del(5q) requires functional RUNX1. Similar results were obtained with TP53 knock-out cells. Both RUNX1 and TP53 transcripts cooperate and alter the activity of GATA2 transcriptional complex [59].


3. Studies on lenalidomide use also in lower risk non-del(5q) MDS treatment and new possible therapies

While CSNK1A1 is CRL4CRBN target in del(5q) MDS, CRL4CRBN targets in lower risk non-del(5q) remain to be determined. The mechanism of action of lenalidomide is still unclear in non-del(5q) MDS cells. Recent evidence shows that lenalidomide directly improves erythropoietin receptor (EPOR) signaling by EPOR upregulation mediated by a posttranscriptional mechanism [62]. Lenalidomide stabilizes the EPOR protein by inhibition of the E3 ubiquitin ligase RNF41 (ring finger protein 41, also known as neuregulin receptor degradation protein-1/Nrdp1/and fetal liver ring finger/FLRF/) responsible for EPOR polyubiquitination and next degradation [62] and induces lipid raft assembly to enhance EPOR signaling in MDS erythroid progenitors [63, 64].

After failure of ESAs, lenalidomide yields red blood cell transfusion independence in 20–30% of lower risk non-del(5q) MDS. Indeed, several observations suggest an additive effect of ESA and lenalidomide in this situation [65, 66] and also in del(5q) MDS patients [67]. Synthetic corticosteroids (dexamethasone and prednisone) are also able to potentiate the effect of lenalidomide or combination of lenalidomide and erythropoietin [67, 68, 69].

Basiorka et al. and Sallman et al. reported activation of the NLRP3 inflammasome in MDS [70, 71]. NRLP3 drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins. Activated NLRP3 complexes direct then activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX) and increasing levels of reactive oxygen species (ROS). ROS initiate cation influx, cell swelling, and β-catenin activation. Knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs cause a common redox-sensitive inflammasome circuit. They are new candidates for therapeutic intervention.

Not only apoptosis and pyroptosis are involved in increased cell death in MDS. Recently, possible further mechanism of cell death, necroptosis, in MDS has been described [72, 73]. Necroptosis is like pyroptosis associated with membrane permeabilization and the release of damage-associated molecular patterns (DAMPs) such as alarmins. Alarmins bind Toll-like receptor 4 (TLR4) and activate the transcription factor NF-κB and inflammation [74].

The effects of lenalidomide in non-del(5q) are thought to be secondary to modulation of the immune system. Hyperactivated T cells inhibit hematopoiesis. Immunosuppressive therapies with antithymocyte globulin alone and in combination with prednisone or cyclosporine show response rates between 25 and 40% [75, 76].

The studies discussed in this and other chapters of this book will help to translate our knowledge of genetic aberrations and of pathophysiological mechanisms in MDS into clinical use in diagnosis, prognosis, and therapy. Novel agents developed on the basis of this knowledge (luspatercept, rigosertib, immune checkpoint inhibitors, venetoclax, and others) are in clinical trials and will help in relapsed/refractory MDS.

The work of our group in this area was supported by the research project for conceptual development of research organization (00023736; Institute of Hematology and Blood Transfusion, Prague) from the Ministry of Health of the Czech Republic.


  1. 1. Bejar R, Steensma DP. Recent developments in myelodysplastic syndromes. Blood. 2014;124(18):2793-2803. DOI: 10.1182/blood-2014-04-522136
  2. 2. Pellagatti A, Boultwood J. The molecular pathogenesis of the myelodysplastic syndromes. European Journal of Haematology. 2015;95(1):3-15. DOI: 10.1111/ejh.12515
  3. 3. Shastri A, Will B, Steidl U, Verma A. Stem and progenitor cell alterations in myelodysplastic syndromes. Blood. 2017;129(12):1586-1594. DOI: 10.1182/blood-2016-10-696062
  4. 4. Nazha A, Sekeres MA. Precision medicine in myelodysplastic syndromes and leukemias: Lessons from sequential mutations. Annual Review of Medicine. 2017;68:127-137. DOI: 10.1146/annurev-med-062915-095637
  5. 5. Nazha A. The MDS genomics-prognosis symbiosis. Hematology. American Society of Hematology. Education Program. 2018:270-276. DOI: 10.1182/asheducation-2018.1.270
  6. 6. Barreyro L, Chlon TM, Starczynowski DT. Chronic immune response dysregulation in MDS pathogenesis. Blood. 2018;132(15):1553-1560. DOI: 10.1182/blood-2018-03-784116
  7. 7. Ganguly BB, Kadam NN. Mutations of myelodysplastic syndromes (MDS): An update. Mutation Research, Reviews in Mutation Research. 2016;769:47-62. DOI: 10.1016/j.mrrev.2016.04.009
  8. 8. Gill H, Leung AY, Kwong YL. Molecular and cellular mechanisms of myelodysplastic syndrome: Implications on targeted therapy. International Journal of Molecular Sciences. 2016;17(4):440. DOI: 10.3390/ijms17040440
  9. 9. Weinberg OK, Hasserjian RP. The current approach to the diagnosis of myelodysplastic syndromes. Seminars in Hematology. 2019;56(1):15-21. DOI: 10.1053/j. seminhematol.2018.05.015
  10. 10. Schanz J, Cevik N, Fonatsch C, Braulke F, Shirneshan K, Bacher U, et al. Detailed analysis of clonal evolution and cytogenetic evolution patterns in patients with myelodysplastic syndromes (MDS) and related myeloid disorders. Blood Cancer Journal. 2018;8(3):28. DOI: 10.1038/s41408-018-0061-z
  11. 11. Steensma DP. Clinical consequences of clonal hematopoiesis of indeterminate potential. Blood Advances. 2018;2(22):3404-3410. DOI: 10.1182/bloodadvances. 2018020222
  12. 12. Valent P. ICUS, IDUS, CHIP and CCUS: Diagnostic criteria, separation from MDS and clinical implications. Pathobiology. 2019;86(1):30-38. DOI: 10.1159/000489042
  13. 13. Patnaik MM, Tefferi A. Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management. American Journal of Hematology. 2017;92(3):297-310. DOI: 10.1002/ajh.24637
  14. 14. Patnaik MM, Tefferi A. Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T)—“2019 update on diagnosis, risk-stratification, and management”. American Journal of Hematology. 2019. DOI: 10.1002/ajh.25397
  15. 15. Nikpour M, Scharenberg C, Liu A, Conte S, Karimi M, Mortera-Blanco T, et al. The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts. Leukemia. 2013;27(4):889-896. DOI: 10.1038/leu.2012.298
  16. 16. Nishiyama T, Ishikawa Y, Kawashima N, Akashi A, Adachi Y, Hattori H, et al. Mutation analysis of therapy-related myeloid neoplasms. Cancer Genetics. 2018;222-223:38-45. DOI: 10.1016/j.cancergen.2018.02.006
  17. 17. Valka J, Vesela J, Votavova H, Dostalova-Merkerova M, Horakova Z, Campr V, et al. Differential expression of homologous recombination DNA repair genes in the early and advanced stages of myelodysplastic syndrome. European Journal of Haematology. 2017;99(4):323-331. DOI: 10.1111/ejh.12920
  18. 18. Ribeiro HL Jr, Maia ARS, de Oliveira RTG, Dos Santos AWA, Costa MB, Farias IR, et al. Expression of DNA repair genes is important molecular findings in CD34+ stem cells of myelodysplastic syndrome. European Journal of Haematology. 2018;100(1):108-109. DOI: 10.1111/ejh.12966
  19. 19. Boultwood J, Pellagatti A, McKenzie AN, Wainscoat JS. Advances in the 5q− syndrome. Blood. 2010;116(26):5803-5811. DOI: 10.1182/blood-2010-04-273771
  20. 20. Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, et al. Identification of miR-145 and miR-146a as mediators of the 5q− syndrome phenotype. Nature Medicine. 2010;16(1):49-58. DOI: 10.1038/nm.2054
  21. 21. Ebert BL. Molecular dissection of the 5q deletion in myelodysplastic syndrome. Seminars in Oncology. 2011;38(5):621-626. DOI: 10.1053/j.seminoncol.2011.04.010
  22. 22. Kumar MS, Narla A, Nonami A, Mullally A, Dimitrova N, Ball B, et al. Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q− syndrome. Blood. 2011;118(17):4666-4673. DOI: 10.1182/blood-2010-12-324715
  23. 23. Fuchs O. Important genes in the pathogenesis of 5q− syndrome and their connection with ribosomal stress and the innate immune system pathway. Leukemia Research and Treatment. 2012;2012:179402. DOI: 10.1155/2012/179402
  24. 24. Neuwirtova R, Fuchs O, Holicka M, Vostry M, Kostecka A, Hajkova H, et al. Transcription factors Fli1 and EKLF in the differentiation of megakaryocytic and erythroid progenitor in 5q− syndrome and in Diamond-Blackfan anemia. Annals of Hematology. 2013;92(1):11-18. DOI: 10.1007/s00277-012-1568-1
  25. 25. Komrokji RS, Padron E, Ebert BL, List AF. Deletion 5q MDS: Molecular and therapeutic implications. Best Practice & Research. Clinical Haematology. 2013;26(4):365-375. DOI: 10.1016/j.beha.2013.10.013
  26. 26. Giagounidis A, Mufti GJ, Fenaux P, Germing U, List A, MacBeth KJ. Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: Linking mechanism of action to clinical outcomes. Annals of Hematology. 2014;93(1):1-11. DOI: 10.1007/s00277-013-1863-5
  27. 27. List AF, Bennett JM, Sekeres MA, Skikne B, Fu T, Shammo JM, et al. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. Leukemia. 2014;28(5):1033-1040. DOI: 10.1038/leu.2013.305
  28. 28. Pellagatti A, Boultwood J. Recent advances in the 5q− syndrome. Mediterranean Journal of Hematology and Infectious Diseases. 2015;7(1):e2015037. DOI: 10.4084/MJHID.2015.037
  29. 29. Varney ME, Niederkorn M, Konno H, Matsumura T, Gohda J, Yoshida N, et al. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. The Journal of Experimental Medicine. 2015;212(11):1967-1985. DOI: 10.1084/jem.20141898
  30. 30. Fink EC, Ebert BL. The novel mechanism of lenalidomide activity. Blood. 2015;126(21):2366-2369. DOI: 10.1182/blood-2015-07-567958
  31. 31. Guirguis AA, Ebert BL. Lenalidomide: Deciphering mechanisms of action in myeloma, myelodysplastic syndrome and beyond. Current Opinion in Cell Biology. 2015;37:61-67. DOI: 10.1016/
  32. 32. Komrokji RS, List AF. Short- and long-term benefits of lenalidomide treatment in patients with lower-risk del(5q) myelodysplastic syndromes. Annals of Oncology. 2016;27(1):62-68. DOI: 10.1093/annonc/mdv488
  33. 33. Talati C, Sallman D, List A. Lenalidomide: Myelodysplastic syndromes with del(5q) and beyond. Seminars in Hematology. 2017;54(3):159-166. DOI: 10.1053/j.seminhematol.2017. 06.003
  34. 34. Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mittelman M, Muus P, et al. Clinical characteristics and outcomes according to age in lenalidomide-treated patients with RBC transfusion-dependent lower-risk MDS and del(5q). Journal of Hematology & Oncology. 2017;10(1):131. DOI: 10.1186/s13045-017-0491-2
  35. 35. Lee JH, List A, Sallman DA. Molecular pathogenesis of myelodysplastic syndromes with deletion 5q. European Journal of Haematology. 2018. DOI: 10.1111/ejh.13207
  36. 36. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, et al. Identification of RPS14 as a 5q− syndrome gene by RNA interference screen. Nature. 2008;451(7176):335-339. DOI: 10.1038/nature06494
  37. 37. Schneider RK, Schenone M, Ferreira MV, Kramann R, Joyce CE, Hartigan C, et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nature Medicine. 2016;22(3):288-297. DOI: 10.1038/nm.4047
  38. 38. Cluzeau T, McGraw KL, Irvine B, Masala E, Ades L, Basiorka AA, et al. Pro-inflammatory proteins S100A9 and tumor necrosis factor-α suppress erythropoietin elaboration in myelodysplastic syndromes. Haematologica. 2017;102(12):2015-2020. DOI: 10.3324/haematol. 2016. 158857
  39. 39. Vlachos A, Farrar JE, Atsidaftos E, Muir E, Narla A, Markello TC, et al. Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q− syndrome. Blood. 2013;122(14):2487-2490. DOI: 10.1182/blood-2013-06-509935
  40. 40. Czibere A, Bruns I, Junge B, Singh R, Kobbe G, Haas R, et al. Low RPS14 expression is common in myelodysplastic syndromes without 5q− aberration and defines a subgroup of patients with prolonged survival. Haematologica. 2009;94(10):1453-1455. DOI: 10.3324/haematol.2009.008508
  41. 41. Wu L, Li X, Xu F, Zhang Z, Chang C, He Q. Low RPS14 expression in MDS without 5q− aberration confers higher apoptosis rate of nucleated erythrocytes and predicts prolonged survival and possible response to lenalidomide in lower risk non-5q− patients. European Journal of Haematology. 2013;90(6):486-493. DOI: 10.1111/ejh.12105
  42. 42. Wei S, Chen X, Rocha K, Epling-Burnette PK, Djeu JY, Liu Q, 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. DOI: 10.1073/pnas.0811267106
  43. 43. Wei S, Chen X, McGraw K, Zhang L, Komrokji R, Clark J, et al. Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. Oncogene. 2013;32(9):1110-1120. DOI: 10.1038/onc. 2012.139
  44. 44. Gandhi AK, Kang J, Naziruddin S, Parton A, Schafer PH, Stirling DI. Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly. Leukemia Research. 2006;30(7):849-858
  45. 45. Matsuoka A, Tochigi A, Kishimoto M, Nakahara T, Kondo T, Tsujioka T, et al. Lenalidomide induces cell death in an MDS-derived cell line with deletion of chromosome 5q by inhibition of cytokinesis. Leukemia. 2010;24(4):748-755. DOI: 10.1038/leu.2009.296
  46. 46. Venner CP, Woltosz JW, Nevill TJ, Deeg HJ, Caceres G, Platzbecker U, et al. Correlation of clinical response and response duration with miR-145 induction by lenalidomide in CD34(+) cells from patients with del(5q) myelodysplastic syndrome. Haematologica. 2013;98(3):409-413. DOI: 10.3324/haematol.2012.066068
  47. 47. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345-1350. DOI: 10.1126/science.1177319
  48. 48. Ito T, Handa H. Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs. International Journal of Hematology. 2016;104(3):293-299. DOI: 10.1007/s12185-016-2073-4
  49. 49. Chang XB, Stewart AK. What is the functional role of the thalidomide binding protein cereblon? International Journal of Biochemistry and Molecular Biology. 2011;2(3):287-294
  50. 50. Kim HK, Ko TH, Nyamaa B, Lee SR, Kim N, Ko KS, et al. Cereblon in health and disease. Pflügers Archiv. 2016;468(8):1299-1309. DOI: 10.1007/s00424-016-1854-1
  51. 51. Jonasova A, Bokorova R, Polak J, Vostry M, Kostecka A, Hajkova H, et al. High level of full-length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide. European Journal of Haematology. 2015;95(1):27-34. DOI: 10.1111/ejh.12457
  52. 52. Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014;512(7512):49-53. DOI: 10.1038/nature13527
  53. 53. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343(6168):301-305. DOI: 10.1126/science. 1244851
  54. 54. Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015;523(7559):183-188. DOI: 10.1038/nature14610
  55. 55. Schneider RK, Ademà V, Heckl D, Järås M, Mallo M, Lord AM, et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell. 2014;26(4):509-520. DOI: 10.1016/j.ccr. 2014.08.001
  56. 56. Smith AE, Kulasekararaj AG, Jiang J, Mian S, Mohamedali A, Gaken J, et al. CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: A retrospective mutational analysis. The Lancet Haematology. 2015;2(5):e212-e221. DOI: 10.1016/S2352-3026(15)00050-2
  57. 57. Heuser M, Meggendorfer M, Cruz MM, Fabisch J, Klesse S, Köhler L, et al. Frequency and prognostic impact of casein kinase 1A1 mutations in MDS patients with deletion of chromosome 5q. Leukemia. 2015;29(9):1942-1945. DOI: 10.1038/leu.2015.49
  58. 58. Negoro E, Radiovoyevitch T, Polprasert C, Adema V, Hosono N, Makishima H, et al. Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide. Leukemia. 2016;30(12):2405-2409. DOI: 10.1038/leu.2016.228
  59. 59. Martinez-Høyer S, Mo A, Deng D, Jiang J, Docking R, Li J, et al. Resistance to lenalidomide in del(5q) MDS is mediated by inhibition of drug-induced megakaryocytic differentiation. Blood. 2018;132:176. DOI: 10.1182/blood-2018-176
  60. 60. List A, Ebert BL, Fenaux P. A decade of progress in myelodysplastic syndrome with chromosome 5q deletion. Leukemia. 2018;32(7):1493-1499. DOI: 10.1038/s41375-018-0029-9
  61. 61. Belickova M, Vesela J, Jonasova A, Pejsova B, Votavova H, Merkerova MD, et al. TP53 mutation variant allele frequency is a potential predictor for clinical outcome of patients with lower-risk myelodysplastic syndromes. Oncotarget. 2016;7(24):36266-36279. DOI: 10.18632/oncotarget.9200
  62. 62. Basiorka AA, McGraw KL, De Ceuninck L, Griner LN, Zhang L, Clark JA, et al. Lenalidomide stabilizes the erythropoietin receptor by inhibiting the E3 ubiquitin ligase RNF41. Cancer Research. 2016;76(12):3531-3540. DOI: 10.1158/0008-5472.CAN-15-1756
  63. 63. McGraw KL, Fuhler GM, Johnson JO, Clark JA, Caceres GC, Sokol L, et al. Erythropoietin receptor signaling is membrane raft dependent. PLoS One. 2012;7(4):e34477. DOI: 10.1371/journal.pone.0034477
  64. 64. McGraw KL, Basiorka AA, Johnson JO, Clark J, Caceres G, Padron E, et al. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors. PLoS One. 2014;9(12):e114249. DOI: 10.1371/journal.pone.0114249
  65. 65. Komrokji RS, Lancet JE, Swern AS, Chen N, Paleveda J, Lush R, et al. Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood. 2012;120(17):3419-3424. DOI: 10.1182/blood-2012-03-415661
  66. 66. Toma A, Kosmider O, Chevret S, Delaunay J, Stamatoullas A, Rose C, et al. Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. Leukemia. 2016;30(4):897-905. DOI: 10.1038/leu.2015.296
  67. 67. Jonasova A, Neuwirtova R, Polackova H, Siskova M, Stopka T, Cmunt E, et al. Lenalidomide treatment in lower risk myelodysplastic syndromes—The experience of a Czech hematology center. (Positive effect of erythropoietin ± prednisone addition to lenalidomide in refractory or relapsed patients). Leukemia Research. 2018;69:12-17. DOI: 10.1016/j.leukres.2018.03.015
  68. 68. Narla A, Dutt S, McAuley JR, Al-Shahrour F, Hurst S, McConkey M, et al. Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis. Blood. 2011;118(8):2296-2304. DOI: 10.1182/blood-2010-11-318543
  69. 69. Komrokji RS, Al Ali NH, Padron E, Cogle C, Tinsley S, Sallman D, et al. Lenalidomide and prednisone in low and intermediate-1 IPSS risk, non-del(5q) MDS patients: A phase II clinical trial. Clinical Lymphoma, Myeloma & Leukemia. 2019. DOI: 10.1016/j.clml.2018.12.014
  70. 70. Basiorka AA, McGraw KL, Eksioglu EA, Chen X, Johnson J, Zhang L, et al. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016;128(25):2960-2975. DOI: 10.1182/blood-2016-07-730556
  71. 71. Sallman DA, Cluzeau T, Basiorka AA, List A. Unraveling the pathogenesis of MDS: The NLRP3 inflammasome and pyroptosis drive the MDS phenotype. Frontiers in Oncology. 2016;6:151. DOI: 10.3389/fonc.2016.00151
  72. 72. Croker BA, Kelliher MA. BID-ding on necroptosis in MDS. Blood. 2019;133(2):103-104. DOI: 10.1182/blood-2018-11-886242
  73. 73. Wagner PN, Shi Q, Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, et al. Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice. Blood. 2019;133(2):107-120. DOI: 10.1182/blood-2018-05-847335
  74. 74. Ping Z, Chen S, Hermans SJF, Kenswil KJG, Feyen J, van Dijk C, et al. Activation of NF-κB driven inflammatory programs in mesenchymal elements attenuates hematopoiesis in low-risk myelodysplastic syndromes. Leukemia. 2018. DOI: 10.1038/s41375-018-0267-x
  75. 75. Haider M, Al Ali N, Padron E, Epling-Burnette P, Lancet J, List A, et al. Immunosuppressive therapy: Exploring an underutilized treatment option for myelodysplastic syndrome. Clinical Lymphoma, Myeloma & Leukemia. 2016;16(Suppl):S44-S48. DOI: 10.1016/j.clml.2016.02.017
  76. 76. Stahl M, Zeidan AM. Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications. Cancer. 2017;123(10):1703-1713. DOI: 10.1002/cncr.30585

Written By

Ota Fuchs

Published: 29 January 2019