Advertisement

Current Hematologic Malignancy Reports

, Volume 13, Issue 6, pp 467–476 | Cite as

Myelodysplastic Syndromes: Laboratory Workup in the Context of New Concepts and Classification Criteria

  • Maria Sanz-De Pedro
  • Wei Wang
  • Rashmi Kanagal-Shamanna
  • Joseph D. KhouryEmail author
Molecular Testing and Diagnostics (J Khoury, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Molecular Testing and Diagnostics

Abstract

Purpose of Review

This review provides a comprehensive update of myelodysplastic syndromes (MDS) and their diagnostic criteria, with emphasis on novel concepts and state-of-the-art laboratory workup, including multiparameter/multicolor flow cytometry, chromosome analysis, and mutation profiling.

Recent Findings

Recent advances in genetics and molecular technologies have provided unprecedented insights into the pathogenic mechanisms and genomic landscape of MDS and its precursor lesions. This has resulted in revised diagnostic criteria in the World Health Organization (WHO) classification and proposed new terminology for early lesions such as clonal hematopoiesis of indeterminate potential (CHIP). Against this landscape, a thorough understanding of the advantages and limitations of laboratory tests employed in the evaluation of patients with cytopenia has gained unprecedented importance.

Summary

Healthcare providers involved in the care of patients with hematologic diseases should be aware of the intricacies of laboratory workup of such patients, particularly in view of the novel concepts and classification criteria of MDS.

Keywords

Myelodysplastic syndrome Classification Molecular diagnostics Cytogenetics Morphology Mutation 

Notes

Acknowledgements

The authors thank Ms. Jessica Rodriguez for editorial assistance.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Supplementary material

11899_2018_483_MOESM1_ESM.docx (32 kb)
ESM 1 (DOCX 31 kb)

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33(4):451–8.PubMedGoogle Scholar
  2. 2.
    Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51(2):189–99.PubMedGoogle Scholar
  3. 3.
    Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press; 2008.Google Scholar
  4. 4.
    Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–51.PubMedGoogle Scholar
  5. 5.
    Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–88.Google Scholar
  6. 6.
    •• Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–65 Landmark publication describing the revised international prognostic scoring system for myelodysplastic syndromes (IPSS-R). PubMedPubMedCentralGoogle Scholar
  7. 7.
    Hasserjian RP, Orazi A, Brunning RD, Germing U, Le Beau MM, Porwit A, et al. Myelodysplastic syndromes. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumors of hematopoietic and lymphoid tissues (revised 4th edition). Lyon: IARC; 2017.Google Scholar
  8. 8.
    Wang W, Wang SA, Medeiros LJ, Khoury JD. Pure erythroid leukemia. Am J Hematol. 2017;92(3):292–6.PubMedGoogle Scholar
  9. 9.
    Kaloutsi V, Kohlmeyer U, Maschek H, Nafe R, Choritz H, Amor A, et al. Comparison of bone marrow and hematologic findings in patients with human immunodeficiency virus infection and those with myelodysplastic syndromes and infectious diseases. Am J Clin Pathol. 1994;101(2):123–9.PubMedGoogle Scholar
  10. 10.
    Greenberg PL, Attar E, Bennett JM, Bloomfield CD, De Castro CM, Deeg HJ, et al. NCCN clinical practice guidelines in oncology: myelodysplastic syndromes. J Natl Compr Cancer Netw. 2011;9(1):30–56.Google Scholar
  11. 11.
    Valent P, Horny HP, Bennett JM, Fonatsch C, Germing U, Greenberg P, et al. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: consensus statements and report from a working conference. Leuk Res. 2007;31(6):727–36.PubMedGoogle Scholar
  12. 12.
    • Loghavi S, Sui D, Wei P, Garcia-Manero G, Pierce S, Routbort MJ, et al. Validation of the 2017 revision of the WHO chronic myelomonocytic leukemia categories. Blood Adv 2018;2(15):1807–16. Validation of the 2017 WHO criteria for CMML showing limited value for the newly introducted CMML-0 subgroup. Google Scholar
  13. 13.
    Malcovati L, Della Porta MG, Strupp C, Ambaglio I, Kuendgen A, Nachtkamp K, et al. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based prognostic scoring system (WPSS). Haematologica. 2011;96(10):1433–40.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Cordoba I, Gonzalez-Porras JR, Such E, Nomdedeu B, Luno E, de Paz R, et al. The degree of neutropenia has a prognostic impact in low risk myelodysplastic syndrome. Leuk Res. 2012;36(3):287–92.PubMedGoogle Scholar
  15. 15.
    Gonzalez-Porras JR, Cordoba I, Such E, Nomdedeu B, Vallespi T, Carbonell F, et al. Prognostic impact of severe thrombocytopenia in low-risk myelodysplastic syndrome. Cancer. 2011;117(24):5529–37.PubMedGoogle Scholar
  16. 16.
    Kantarjian H, Giles F, List A, Lyons R, Sekeres MA, Pierce S, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007;109(9):1705–14.PubMedGoogle Scholar
  17. 17.
    Kao JM, McMillan A, Greenberg PL. International MDS risk analysis workshop (IMRAW)/IPSS reanalyzed: impact of cytopenias on clinical outcomes in myelodysplastic syndromes. Am J Hematol. 2008;83(10):765–70.PubMedGoogle Scholar
  18. 18.
    Saeed L, Patnaik MM, Begna KH, Al-Kali A, Litzow MR, Hanson CA, et al. Prognostic relevance of lymphocytopenia, monocytopenia and lymphocyte-to-monocyte ratio in primary myelodysplastic syndromes: a single center experience in 889 patients. Blood Cancer J. 2017;7(3):e550.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Malcovati L, Hellstrom-Lindberg E, Bowen D, Ades L, Cermak J, Del Canizo C, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943–64.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Germing U, Hildebrandt B, Pfeilstocker M, Nosslinger T, Valent P, Fonatsch C, et al. Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS). Leukemia. 2005;19(12):2223–31.PubMedGoogle Scholar
  21. 21.
    Wimazal F, Sperr WR, Kundi M, Vales A, Fonatsch C, Thalhammer-Scherrer R, et al. Prognostic significance of serial determinations of lactate dehydrogenase (LDH) in the follow-up of patients with myelodysplastic syndromes. Ann Oncol. 2008;19(5):970–6.PubMedGoogle Scholar
  22. 22.
    Neukirchen J, Blum S, Kuendgen A, Strupp C, Aivado M, Haas R, et al. Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes. Eur J Haematol. 2009;83(5):477–82.PubMedGoogle Scholar
  23. 23.
    Al Ameri A, Jabbour E, Garcia-Manero G, O'Brien S, Faderl S, Ravandi F, et al. Significance of thrombocytopenia in myelodysplastic syndromes: associations and prognostic implications. Clin Lymphoma Myeloma Leuk. 2011;11(2):237–41.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Manoharan A, Brighton T, Gemmell R, Lopez K, Moran S, Kyle P. Platelet dysfunction in myelodysplastic syndromes: a clinicopathological study. Int J Hematol. 2002;76(3):272–8.PubMedGoogle Scholar
  25. 25.
    Dutt S, Narla A, Lin K, Mullally A, Abayasekara N, Megerdichian C, et al. Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood. 2011;117(9):2567–76.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Zeidman A, Sokolover N, Fradin Z, Cohen A, Redlich O, Mittelman M. Platelet function and its clinical significance in the myelodysplastic syndromes. Hematol J. 2004;5(3):234–8.PubMedGoogle Scholar
  27. 27.
    Meschengieser S, Blanco A, Maugeri N, Dupont J, Fernandez J, de Tezanos Pinto M, et al. Platelet function and intraplatelet von Willebrand factor antigen and fibrinogen in myelodysplastic syndromes. Thromb Res. 1987;46(4):601–6.PubMedGoogle Scholar
  28. 28.
    de Cataldo F, Baudo F, Redaelli R, Corno AR. Abnormal platelet von Willebrand factor (vWF) as a marker of abnormal function in megakaryocytic dysplasia. Am J Hematol. 1995;48(3):155–7.PubMedGoogle Scholar
  29. 29.
    Brummitt DR, Barker HF. The determination of a reference range for new platelet parameters produced by the Bayer ADVIA120 full blood count analyser. Clin Lab Haematol. 2000;22(2):103–7.PubMedGoogle Scholar
  30. 30.
    Curvers J, de Wildt-Eggen J, Heeremans J, Scharenberg J, de Korte D, van der Meer PF. Flow cytometric measurement of CD62P (P-selectin) expression on platelets: a multicenter optimization and standardization effort. Transfusion. 2008;48(7):1439–46.PubMedGoogle Scholar
  31. 31.
    Sugimori N, Kondo Y, Shibayama M, Omote M, Takami A, Sugimori C, et al. Aberrant increase in the immature platelet fraction in patients with myelodysplastic syndrome: a marker of karyotypic abnormalities associated with poor prognosis. Eur J Haematol. 2009;82(1):54–60.PubMedGoogle Scholar
  32. 32.
    Alayed K, Patel KP, Konoplev S, Singh RR, Routbort MJ, Reddy N, et al. TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow. Am J Hematol. 2013;88(12):1055–61.PubMedGoogle Scholar
  33. 33.
    Khoury JD, Sen F, Abruzzo LV, Hayes K, Glassman A, Medeiros LJ. Cytogenetic findings in blastoid mantle cell lymphoma. Hum Pathol. 2003;34(10):1022–9.PubMedGoogle Scholar
  34. 34.
    Tang Z, Tang G, Wang SA, Lu X, Young KH, Bueso-Ramos CE, et al. Simultaneous deletion of 3'ETV6 and 5'EWSR1 genes in blastic plasmacytoid dendritic cell neoplasm: case report and literature review. Mol Cytogenet. 2016;9:23.PubMedPubMedCentralGoogle Scholar
  35. 35.
    van Dongen JJ, Lhermitte L, Bottcher S, Almeida J, van der Velden VH, Flores-Montero J, et al. EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26(9):1908–75.PubMedPubMedCentralGoogle Scholar
  36. 36.
    • Porwit A, van de Loosdrecht AA, Bettelheim P, Brodersen LE, Burbury K, Cremers E, et al. Revisiting guidelines for integration of flow cytometry results in the WHO classification of myelodysplastic syndromes-proposal from the International/European LeukemiaNet Working Group for Flow Cytometry in MDS. Leukemia. 2014;28(9):1793–8. Consensus criteria for flow cytometry studies in the evaluation of patients with MDS. PubMedGoogle Scholar
  37. 37.
    van de Loosdrecht AA, Alhan C, Bene MC, Della Porta MG, Drager AM, Feuillard J, et al. Standardization of flow cytometry in myelodysplastic syndromes: report from the first European LeukemiaNet working conference on flow cytometry in myelodysplastic syndromes. Haematologica. 2009;94(8):1124–34.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Westers TM, Ireland R, Kern W, Alhan C, Balleisen JS, Bettelheim P, et al. Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group. Leukemia. 2012;26(7):1730–41.PubMedGoogle Scholar
  39. 39.
    van de Loosdrecht AA, Westers TM. Cutting edge: flow cytometry in myelodysplastic syndromes. J Natl Compr Cancer Netw. 2013;11(7):892–902.Google Scholar
  40. 40.
    Chu SC, Wang TF, Li CC, Kao RH, Li DK, Su YC, et al. Flow cytometric scoring system as a diagnostic and prognostic tool in myelodysplastic syndromes. Leuk Res. 2011;35(7):868–73.PubMedGoogle Scholar
  41. 41.
    Ogata K, Della Porta MG, Malcovati L, Picone C, Yokose N, Matsuda A, et al. Diagnostic utility of flow cytometry in low-grade myelodysplastic syndromes: a prospective validation study. Haematologica. 2009;94(8):1066–74.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Wells DA, Benesch M, Loken MR, Vallejo C, Myerson D, Leisenring WM, et al. Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation. Blood. 2003;102(1):394–403.PubMedGoogle Scholar
  43. 43.
    van de Loosdrecht AA, Westers TM, Westra AH, Drager AM, van der Velden VH, Ossenkoppele GJ. Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry. Blood 2008;111(3):1067–1077.Google Scholar
  44. 44.
    Della Porta MG, Picone C, Pascutto C, Malcovati L, Tamura H, Handa H, et al. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study. Haematologica. 2012;97(8):1209–17.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Aldawood AM, Kinkade Z, Rosado FG, Esan OA, Gibson LF, Vos JA. A novel method to assess bone marrow purity is useful in determining blast percentage by flow cytometry in acute myeloid leukemia and myelodysplasia. Ann Hematol Oncol. 2015;2(5).Google Scholar
  46. 46.
    Brooimans RA, Kraan J, van Putten W, Cornelissen JJ, Lowenberg B, Gratama JW. Flow cytometric differential of leukocyte populations in normal bone marrow: influence of peripheral blood contamination. Cytometry B Clin Cytom 2009;76(1):18–26.Google Scholar
  47. 47.
    Loken MR, Chu SC, Fritschle W, Kalnoski M, Wells DA. Normalization of bone marrow aspirates for hemodilution in flow cytometric analyses. Cytometry B Clin Cytom. 2009;76(1):27–36.PubMedGoogle Scholar
  48. 48.
    Loken MR, van de Loosdrecht A, Ogata K, Orfao A, Wells DA. Flow cytometry in myelodysplastic syndromes: report from a working conference. Leuk Res. 2008;32(1):5–17.PubMedGoogle Scholar
  49. 49.
    Kern W, Haferlach C, Schnittger S, Alpermann T, Haferlach T. Serial assessment of suspected myelodysplastic syndromes: significance of flow cytometric findings validated by cytomorphology, cytogenetics, and molecular genetics. Haematologica. 2013;98(2):201–7.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Stetler-Stevenson M, Arthur DC, Jabbour N, Xie XY, Molldrem J, Barrett AJ, et al. Diagnostic utility of flow cytometric immunophenotyping in myelodysplastic syndrome. Blood. 2001;98(4):979–87.PubMedGoogle Scholar
  51. 51.
    Malcovati L, Della Porta MG, Lunghi M, Pascutto C, Vanelli L, Travaglino E, et al. Flow cytometry evaluation of erythroid and myeloid dysplasia in patients with myelodysplastic syndrome. Leukemia. 2005;19(5):776–83.PubMedGoogle Scholar
  52. 52.
    Westers TM, van der Velden VH, Alhan C, Bekkema R, Bijkerk A, Brooimans RA, et al. Implementation of flow cytometry in the diagnostic work-up of myelodysplastic syndromes in a multicenter approach: report from the Dutch Working Party on Flow Cytometry in MDS. Leuk Res. 2012;36(4):422–30.PubMedGoogle Scholar
  53. 53.
    Karai B, Szantho E, Kappelmayer J, Hevessy Z. Flow cytometry in the diagnosis of myelodysplastic syndromes. EJIFCC. 2013;23(4):109–16.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Alhan C, Westers TM, Cremers EM, Cali C, Witte BI, Ossenkoppele GJ, et al. The myelodysplastic syndromes flow cytometric score: a three-parameter prognostic flow cytometric scoring system. Leukemia. 2016;30(3):658–65.PubMedGoogle Scholar
  55. 55.
    Mathis S, Chapuis N, Debord C, Rouquette A, Radford-Weiss I, Park S, et al. Flow cytometric detection of dyserythropoiesis: a sensitive and powerful diagnostic tool for myelodysplastic syndromes. Leukemia. 2013;27(10):1981–7.PubMedGoogle Scholar
  56. 56.
    Kanagal-Shamanna R, Bueso-Ramos CE, Barkoh B, Lu G, Wang S, Garcia-Manero G, et al. Myeloid neoplasms with isolated isochromosome 17q represent a clinicopathologic entity associated with myelodysplastic/myeloproliferative features, a high risk of leukemic transformation, and wild-type TP53. Cancer. 2012;118(11):2879–88.PubMedGoogle Scholar
  57. 57.
    Tang Z, Medeiros LJ, Yin CC, Wang W, Lu X, Young KH, et al. Sex chromosome loss after allogeneic hematopoietic stem cell transplant in patients with hematologic neoplasms: a diagnostic dilemma for clinical cytogeneticists. Mol Cytogenet. 2016;9:62.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Yin CC, Peng J, Li Y, Shamanna RK, Muzzafar T, DiNardo C, et al. Clinical significance of newly emerged isolated del(20q) in patients following cytotoxic therapies. Mod Pathol. 2016;29(8):939.PubMedGoogle Scholar
  59. 59.
    Tang Z, Li Y, Wang SA, Hu S, Li S, Lu X, et al. Clinical significance of acquired loss of the X chromosome in bone marrow. Leuk Res. 2016;47:109–13.PubMedGoogle Scholar
  60. 60.
    Yin CC, Peng J, Li Y, Kanagal-Shamanna R, Muzzafar T, DiNardo C, et al. Clinical significance of newly emerged isolated del(20q) in patients following cytotoxic therapies. Mod Pathol. 2015;28(8):1014–22.PubMedGoogle Scholar
  61. 61.
    Wang W, Cortes JE, Tang G, Khoury JD, Wang S, Bueso-Ramos CE, et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016;127(22):2742–50.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet. 2012;44(6):642–50.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B, et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet. 2012;44(6):651–8.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Cazzola M, Della Porta MG, Malcovati L. The genetic basis of myelodysplasia and its clinical relevance. Blood. 2013;122(25):4021–34.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616–27 quiz 99.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Khoury JD, Wang WL, Prieto VG, Medeiros LJ, Kalhor N, Hameed M, et al. Validation of immunohistochemical assays for integral biomarkers in the NCI-MATCH EAY131 clinical trial. Clin Cancer Res. 2018;24(3):521–31.PubMedGoogle Scholar
  67. 67.
    Khoury JD. The evolving potential of companion diagnostics. Scand J Clin Lab Invest Suppl. 2016;245:S22–5.PubMedGoogle Scholar
  68. 68.
    Khoury JD, Catenacci DV. Next-generation companion diagnostics: promises, challenges, and solutions. Arch Pathol Lab Med. 2015;139(1):11–3.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Loghavi S, Al-Ibraheemi A, Zuo Z, Garcia-Manero G, Yabe M, Wang SA, et al. TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis. Br J Haematol. 2015;171(1):91–9.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Malcovati L, Karimi M, Papaemmanuil E, Ambaglio I, Jadersten M, Jansson M, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015;126(2):233–41.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Gerstung M, Pellagatti A, Malcovati L, Giagounidis A, Porta MG, Jadersten M, et al. Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes. Nat Commun. 2015;6:5901.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Bains A, Luthra R, Medeiros LJ, Zuo Z. FLT3 and NPM1 mutations in myelodysplastic syndromes: frequency and potential value for predicting progression to acute myeloid leukemia. Am J Clin Pathol. 2011;135(1):62–9.PubMedGoogle Scholar
  73. 73.
    Forghieri F, Paolini A, Morselli M, Bigliardi S, Bonacorsi G, Leonardi G, et al. NPM1 mutations may reveal acute myeloid leukemia in cases otherwise morphologically diagnosed as myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms. Leuk Lymphoma. 2015;56(11):3222–6.PubMedGoogle Scholar
  74. 74.
    •• Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364(26):2496–506 Landmark publication describing the clinical implications of somatic mutations in MDS. PubMedPubMedCentralGoogle Scholar
  75. 75.
    Walter MJ, Shen D, Shao J, Ding L, White BS, Kandoth C, et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia. 2013;27(6):1275–82.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241–7.PubMedGoogle Scholar
  77. 77.
    Pellagatti A, Roy S, Di Genua C, Burns A, McGraw K, Valletta S, et al. Targeted resequencing analysis of 31 genes commonly mutated in myeloid disorders in serial samples from myelodysplastic syndrome patients showing disease progression. Leukemia. 2016;30(1):247–50.PubMedGoogle Scholar
  78. 78.
    Thol F, Kade S, Schlarmann C, Loffeld P, Morgan M, Krauter J, et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood. 2012;119(15):3578–84.PubMedGoogle Scholar
  79. 79.
    Damm F, Thol F, Kosmider O, Kade S, Loffeld P, Dreyfus F, et al. SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications. Leukemia. 2012;26(5):1137–40.PubMedGoogle Scholar
  80. 80.
    Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C, et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood. 2011;118(24):6239–46.PubMedPubMedCentralGoogle Scholar
  81. 81.
    • Hou HA, Tsai CH, Lin CC, Chou WC, Kuo YY, Liu CY, et al. Incorporation of mutations in five genes in the revised International Prognostic Scoring System can improve risk stratification in the patients with myelodysplastic syndrome. Blood Cancer J. 2018;8(4):39. Proposed system for including mutation results in risk-stratification of patients with MDS. PubMedPubMedCentralGoogle Scholar
  82. 82.
    •• Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98 Seminal paper on the clinical implications of clonal hematopoiesis. PubMedPubMedCentralGoogle Scholar
  83. 83.
    Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44(11):1179–81.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472–8.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377(2):111–21.PubMedGoogle Scholar
  87. 87.
    Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506(7488):328–33.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16.PubMedPubMedCentralGoogle Scholar
  89. 89.
    McKerrell T, Park N, Moreno T, Grove CS, Ponstingl H, Stephens J, et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 2015;10(8):1239–45.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Greenberg PL, Stone RM, Al-Kali A, Barta SK, Bejar R, Bennett JM, et al. Myelodysplastic syndromes, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15(1):60–87.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Maria Sanz-De Pedro
    • 1
  • Wei Wang
    • 2
  • Rashmi Kanagal-Shamanna
    • 2
  • Joseph D. Khoury
    • 2
    Email author
  1. 1.Department of Laboratory MedicineLa Paz University HospitalMadridSpain
  2. 2.Department of HematopathologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations