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 (
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
We lack clinical methods to stop clonal development from relatively benign state of CHIP to malignancy. Especially,
MDS are associated with genomic instability and extensive DNA damage caused by deficient repair mechanisms. Aberrations in DNA damage response/repair genes other than
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
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
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
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
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.
References
- 1.
Bejar R, Steensma DP. Recent developments in myelodysplastic syndromes. Blood. 2014; 124 (18):2793-2803. DOI: 10.1182/blood-2014-04-522136 - 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.
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.
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.
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.
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.
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.
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.
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.
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.
Steensma DP. Clinical consequences of clonal hematopoiesis of indeterminate potential. Blood Advances. 2018; 2 (22):3404-3410. DOI: 10.1182/bloodadvances. 2018020222 - 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Fink EC, Ebert BL. The novel mechanism of lenalidomide activity. Blood. 2015; 126 (21):2366-2369. DOI: 10.1182/blood-2015-07-567958 - 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/j.ceb.2015.10.004 - 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Croker BA, Kelliher MA. BID-ding on necroptosis in MDS. Blood. 2019; 133 (2):103-104. DOI: 10.1182/blood-2018-11-886242 - 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.
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.
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.
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