title: Novel therapeutic strategies in myelodysplastic syndromes: do molecular genetics help?
abstract: OBJECTIVE
  Many studies over the past decade have together identified genes that are recurrently mutated in the myelodysplastic syndromes (MDS). We will summarize how this information has informed our understanding of disease pathogenesis and behavior, with an emphasis on how this information may inform therapeutic strategies.
  
  
  RESULTS
  Genomic sequencing techniques have allowed for the identification of many recurrently mutated genes in MDS, with the most common mutations being found in epigenetic modifiers and components of the splicing machinery. Although many mutations are associated with clinical outcomes and disease phenotypes, at the current time they add relatively little to already robust clinical prognostic algorithms. However, as molecular genetic data are accumulated in larger numbers of patients, it is likely that the clinical significance of co-occurring mutations and less common mutations will come to light. Finally, mutated genes may identify biologically distinct subgroups of MDS that may benefit from novel therapies, and a subset of these genes may themselves serve as therapeutic targets.
  
  
  CONCLUSIONS
  Advances in our knowledge of the molecular genetics of MDS have significantly improved our understanding of disease biology and promise to improve tools for clinical decision-making and identify new therapies for patients.
authors.affiliation: aHuman Oncology and Pathogenesis Program bLeukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Chung
mesh_terms: D000818:Animals; D060965:Clonal Evolution / Q000235:genetics; D003131:Combined Modality Therapy; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D023281:Genomics / Q000379:methods; D006801:Humans; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D011379:Prognosis
references.citation: N Engl J Med. 2010 Dec 16;363(25):2424-33
references.pmid: 21067377
references.citation: Lancet Oncol. 2015 Sep;16(9):1099-110
references.pmid: 26296954
references.citation: N Engl J Med. 2006 Oct 5;355(14):1456-65
references.pmid: 17021321
references.citation: Br J Haematol. 2009 Jun;145(6):788-800
references.pmid: 19388938
references.citation: Leukemia. 2014 Jan;28(1):78-87
references.pmid: 24045501
references.citation: Cancer Cell. 2011 Jan 18;19(1):17-30
references.pmid: 21251613
references.citation: Br J Haematol. 2013 Mar;160(5):660-72
references.pmid: 23297687
references.citation: J Clin Oncol. 2002 May 15;20(10):2429-40
references.pmid: 12011120
references.citation: N Engl J Med. 2011 Jun 30;364(26):2496-506
references.pmid: 21714648
references.citation: Blood. 2000 Sep 15;96(6):2012-21
references.pmid: 10979941
references.citation: Science. 2011 Sep 2;333(6047):1303-7
references.pmid: 21817016
references.citation: Science. 2014 May 9;344(6184):649-52
references.pmid: 24797481
references.citation: Cell Cycle. 2011 Aug 15;10 (16):2662-8
references.pmid: 21811096
references.citation: J Clin Oncol. 2014 Sep 1;32(25):2691-8
references.pmid: 25092778
references.citation: Cancer Cell. 2010 Mar 16;17 (3):225-34
references.pmid: 20171147
references.citation: Blood. 2004 Jul 15;104(2):579-85
references.pmid: 15039286
references.citation: Nat Genet. 2009 Jul;41(7):838-42
references.pmid: 19483684
references.citation: J Clin Invest. 2015 May;125(5):1857-72
references.pmid: 25822018
references.citation: Leuk Lymphoma. 2003 Jun;44(6):915-22
references.pmid: 12854888
references.citation: N Engl J Med. 2014 Dec 25;371(26):2477-87
references.pmid: 25426838
references.citation: Blood. 2013 Nov 21;122(22):3616-27; quiz 3699
references.pmid: 24030381
references.citation: Blood. 2009 Jul 2;114(1):144-7
references.pmid: 19420352
references.citation: Haematologica. 2011 Dec;96(12):1870-3
references.pmid: 21880636
references.citation: Leuk Res. 2012 Jan;36(1):1-5
references.pmid: 21920601
references.citation: Br J Haematol. 2005 Jul;130(2):209-17
references.pmid: 16029449
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):3011-6
references.pmid: 23388639
references.citation: N Engl J Med. 2009 May 28;360(22):2289-301
references.pmid: 19474426
references.citation: Br J Haematol. 2013 Aug;162(4):517-24
references.pmid: 23789936
references.citation: N Engl J Med. 2011 Dec 29;365(26):2497-506
references.pmid: 22150006
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2548-53
references.pmid: 24550281
references.citation: Leukemia. 2011 Jul;25(7):1200-2
references.pmid: 21455215
references.citation: N Engl J Med. 2012 Mar 22;366(12):1090-8
references.pmid: 22417201
references.citation: Nature. 2011 Sep 11;478(7367):64-9
references.pmid: 21909114
references.citation: Lancet Oncol. 2009 Mar;10(3):223-32
references.pmid: 19230772
references.citation: J Clin Oncol. 2011 Jun 20;29(18):2499-506
references.pmid: 21576631
references.citation: EMBO Rep. 2011 May;12(5):463-9
references.pmid: 21460794
references.citation: Nat Genet. 2011 Dec 11;44(1):47-52
references.pmid: 22158541
references.citation: Nat Genet. 2010 Aug;42(8):665-7
references.pmid: 20601954
references.citation: Blood. 2009 Oct 15;114(16):3448-58
references.pmid: 19652201
references.citation: Cancer Res. 2011 Feb 1;71(3):955-63
references.pmid: 21189329
references.citation: Nature. 2009 Dec 10;462(7274):739-44
references.pmid: 19935646
references.citation: J Clin Oncol. 2011 May 20;29(15):1971-9
references.pmid: 21519010
references.citation: Nat Med. 2014 Apr;20(4):408-14
references.pmid: 24658078
references.citation: N Engl J Med. 2009 Sep 10;361(11):1058-66
references.pmid: 19657110
references.citation: Leukemia. 2010 May;24(5):1094-6
references.pmid: 20376084
references.citation: N Engl J Med. 2010 Sep 9;363(11):1025-37
references.pmid: 20825315
references.citation: Oncotarget. 2015 Sep 8;6(26):22734-49
references.pmid: 26068951
references.citation: Science. 2011 Sep 2;333(6047):1300-3
references.pmid: 21778364
references.citation: Sci Transl Med. 2012 Aug 29;4(149):149ra118
references.pmid: 22932223
references.citation: Nat Genet. 2011 Dec 11;44(1):53-7
references.pmid: 22158538
references.citation: Cancer Cell. 2015 May 11;27(5):631-43
references.pmid: 25965570
references.citation: Haematologica. 2015 Jul;100(7):945-54
references.pmid: 25862704
references.citation: J Clin Oncol. 2010 Feb 1;28(4):605-13
references.pmid: 20038729
references.citation: N Engl J Med. 2015 Feb 12;372(7):601-12
references.pmid: 25671252
references.citation: Cancer Cell. 2012 Aug 14;22(2):180-93
references.pmid: 22897849
references.citation: Leukemia. 2003 May;17(5):910-8
references.pmid: 12750705
references.citation: Ann Hematol. 2012 Apr;91(4):519-25
references.pmid: 21997850
references.citation: J Clin Oncol. 2012 Sep 20;30(27):3376-82
references.pmid: 22869879
references.citation: Blood. 2011 Oct 6;118(14):3824-31
references.pmid: 21828134
references.citation: Cancer Cell. 2015 May 11;27(5):617-30
references.pmid: 25965569
references.citation: Hematol Oncol. 2015 Jun;33(2):57-66
references.pmid: 24777753
references.citation: Leukemia. 2014 Feb;28(2):241-7
references.pmid: 24220272
references.citation: Leukemia. 2011 Jul;25(7):1153-8
references.pmid: 21415852
references.citation: Blood. 2012 Sep 20;120(12):2454-65
references.pmid: 22740453
references.citation: Leukemia. 2011 Jul;25(7):1147-52
references.pmid: 21494260
references.citation: Eur J Haematol. 2006 Jan;76(1):23-32
references.pmid: 16343268
references.citation: Blood. 1997 Mar 15;89(6):2079-88
references.pmid: 9058730
references.citation: Nat Med. 2014 Apr;20(4):398-407
references.pmid: 24658077
references.citation: Nat Genet. 2010 Aug;42(8):722-6
references.pmid: 20601953
references.citation: Cancer Cell. 2014 Jun 16;25(6):794-808
references.pmid: 24835589
references.citation: N Engl J Med. 2011 Oct 13;365(15):1384-95
references.pmid: 21995386
references.citation: Blood. 2012 Oct 11;120(15):3080-8
references.pmid: 22919025
references.citation: Leukemia. 2013 Jun;27(6):1275-82
references.pmid: 23443460
references.citation: Leukemia. 2009 Jul;23(7):1343-5
references.pmid: 19295549
references.citation: N Engl J Med. 2014 Dec 25;371(26):2488-98
references.pmid: 25426837
references.citation: J Clin Oncol. 2009 Aug 10;27(23):3842-8
references.pmid: 19528372
references.citation: Genes Chromosomes Cancer. 2014 May;53(5):402-10
references.pmid: 24493299
references.citation: Blood. 2012 Apr 5;119(14 ):3203-10
references.pmid: 22323480
references.citation: Leukemia. 2010 May;24(5):1062-5
references.pmid: 20182461
references.citation: Blood. 2009 Jun 18;113(25):6403-10
references.pmid: 19372255
references.citation: Science. 2009 May 15;324(5929):930-5
references.pmid: 19372391
references.citation: Blood. 2009 Feb 5;113(6):1315-25
references.pmid: 18832655
references.citation: Blood. 2012 Apr 5;119(14 ):3211-8
references.pmid: 22343920
references.citation: Cell Stem Cell. 2015 Aug 6;17(2):165-77
references.pmid: 26165925
references.citation: Leukemia. 2003 Sep;17(9):1813-9
references.pmid: 12970781
references.citation: N Engl J Med. 2008 May 1;358(18):1909-18
references.pmid: 18450602
references.citation: Haematologica. 2014 Jun;99(6):1041-9
references.pmid: 24682512
references.citation: Blood. 2012 May 10;119(19):4480-5
references.pmid: 22431577
references.citation: Nature. 2014 Feb 20;506(7488):328-33
references.pmid: 24522528
references.citation: Leukemia. 2012 Jan;26(1):101-5
references.pmid: 22033490
references.citation: Int J Hematol. 2012 Jan;95(1):26-33
references.pmid: 22218883
references.citation: Nature. 2015 Jul 9;523(7559):183-8
references.pmid: 26131937
references.citation: Blood. 2012 Apr 12;119(15):3578-84
references.pmid: 22389253