Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 678

The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

Open access
Sperling, Adam S., Gibson, Christopher J., Ebert, Benjamin L.·2017·Nature Reviews Cancer
DOI 10.1038/nrc.2016.112
Open this paper in CoChat — free account

Abstract

Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nrc.2016.112

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 45 references

Research works printed but not linked: 156

  1. Liew, E. & Owen, C. Familial myelodysplastic syndromes: a review of the literature. Haematologica 96, 1536–1542 (2011). · DOI
  2. Cogle, C. R. Incidence and burden of the myelodysplastic syndromes. Curr. Hematol. Malignancy Rep. 10, 272–281 (2015). · DOI
  3. Ma, X., Does, M., Raza, A. & Mayne, S. T. Myelodysplastic syndromes: incidence and survival in the United States. Cancer 109, 1536–1542 (2007). · DOI · Paper page
  4. Sekeres, M. A. Epidemiology, natural history, and practice patterns of patients with myelodysplastic syndromes in 2010. J. Natl Compr. Canc. Netw. 9, 57–63 (2011). · DOI
  5. Greenberg, P. L. et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120, 2454–2465 (2012). · DOI · Paper page
  6. Kantarjian, H. et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer 113, 1351–1361 (2008). · DOI
  7. Malcovati, L. 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 96, 1433–1440 (2011). · DOI
  8. Bejar, R. et al. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J. Clin. Oncol. 30, 3376–3382 (2012). · DOI · Paper page
  9. Woll, P. S. et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell 25, 794–808 (2014). This paper describes the most detailed characterization of MDS stem cells. · DOI
  10. Miyamoto, T., Weissman, I. L. & Akashi, K. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc. Natl Acad. Sci. USA 97, 7521–7526 (2000). · DOI · Paper page
  11. Nilsson, L. et al. Involvement and functional impairment of the CD34+CD38−Thy-1+ hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8. Blood 100, 259–267 (2002). · DOI
  12. Nilsson, L. et al. Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. Blood 96, 2012–2021 (2000). · DOI
  13. Odejide, O. et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 123, 1293–1296 (2014). · DOI · Paper page
  14. Quivoron, C. et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20, 25–38 (2011). · DOI · Paper page
  15. Steensma, D. P. Myelodysplastic syndromes: diagnosis and treatment. Mayo Clin. Proc. 90, 969–983 (2015). · DOI
  16. Busque, L. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44, 1179–1181 (2012). · DOI · Paper page
  17. Steensma, D. P. et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126, 9–16 (2015). · DOI · Paper page
  18. Cargo, C. A. et al. Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression. Blood 126, 2362–2365 (2015). · DOI
  19. Kwok, B. et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood 126, 2355–2361 (2015). · DOI · Paper page
  20. Papaemmanuil, E. et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616–3627 (2013). Identification of early and late mutations in MDS using variant allele fractions. · DOI · Paper page
  21. Hughes, A. E. et al. Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing. PLoS Genet. 10, e1004462 (2014). · DOI
  22. Lindsley, R. C. et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125, 1367–1376 (2015). Characterization of different mutational spectra found in de novo AML and sAML. · DOI · Paper page
  23. Corces-Zimmerman, M. R., Hong, W. J., Weissman, I. L., Medeiros, B. C. & Majeti, R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc. Natl Acad. Sci. USA 111, 2548–2553 (2014). · DOI · Paper page
  24. Murphy, D. M. et al. NRAS mutations with low allele burden have independent prognostic significance for patients with lower risk myelodysplastic syndromes. Leukemia 27, 2077–2081 (2013). · DOI
  25. Takahashi, K. et al. Dynamic acquisition of FLT3 or RAS alterations drive a subset of patients with lower risk MDS to secondary AML. Leukemia 27, 2081–2083 (2013). · DOI
  26. Gerstung, M. et al. Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes. Nat. Commun. 6, 5901 (2015). · DOI
  27. Kon, A. et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat. Genet. 45, 1232–1237 (2013). · DOI
  28. Bejar, R. et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J. Clin. Oncol. 32, 2691–2698 (2014). · DOI · Paper page
  29. Ortmann, C. A. et al. Effect of mutation order on myeloproliferative neoplasms. N. Engl. J. Med. 372, 601–612 (2015). The first demonstration that mutational order alters clinical phenotype and outcomes in MPN. · DOI · Paper page
  30. Jeromin, S. et al. Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations. Haematologica 100, e125–e127 (2015). · DOI
  31. Garg, M. et al. Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. Blood 126, 2491–2501 (2015). · DOI
  32. Klco, J. M. et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA 314, 811–822 (2015). · DOI
  33. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007). · DOI
  34. Colla, S. et al. Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. Cancer Cell 27, 644–657 (2015). · DOI · Paper page
  35. Inoue, D., Bradley, R. K. & Abdel-Wahab, O. Spliceosomal gene mutations in myelodysplasia: molecular links to clonal abnormalities of hematopoiesis. Genes Dev. 30, 989–1001 (2016). · DOI
  36. Graubert, T. A. et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat. Genet. 44, 53–57 (2012). · DOI · Paper page
  37. Conte, S. et al. Aberrant splicing of genes involved in haemoglobin synthesis and impaired terminal erythroid maturation in SF3B1 mutated refractory anaemia with ring sideroblasts. Br. J. Haematol. 171, 478–490 (2015). · DOI
  38. Darman, R. B. et al. Cancer-associated SF3B1 hotspot mutations induce cryptic 3' splice site selection through use of a different branch point. Cell Rep. 13, 1033–1045 (2015). · DOI
  39. Ilagan, J. O. et al. U2AF1 mutations alter splice site recognition in hematological malignancies. Genome Res. 25, 14–26 (2015). · DOI · Paper page
  40. Przychodzen, B. et al. Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. Blood 122, 999–1006 (2013). · DOI
  41. Yang, L., Rau, R. & Goodell, M. A. DNMT3A in haematological malignancies. Nat. Rev. Cancer 15, 152–165 (2015). · DOI
  42. Walter, M. J. et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25, 1153–1158 (2011). · DOI · Paper page
  43. Ko, M. et al. TET proteins and 5-methylcytosine oxidation in hematological cancers. Immunol. Rev. 263, 6–21 (2015). · DOI
  44. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009). · DOI · Paper page
  45. Ono, R. et al. LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res. 62, 4075–4080 (2002).
  46. Okano, M., Xie, S. & Li, E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat. Genet. 19, 219–220 (1998). · DOI
  47. Yamazaki, J. et al. TET2 mutations affect non-CpG island DNA methylation at enhancers and transcription factor-binding sites in chronic myelomonocytic leukemia. Cancer Res. 75, 2833–2843 CAN-14-0739 (2015). · DOI · Paper page
  48. Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2012). · DOI · Paper page
  49. Zhang, X. et al. DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells. Nat. Genet. 48, 1014–1023 (2016). · DOI · Paper page
  50. Jeong, M. et al. Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat. Genet. 46, 17–23 (2014). · DOI · Paper page
  51. Francis, N. J., Kingston, R. E. & Woodcock, C. L. Chromatin compaction by a polycomb group protein complex. Science 306, 1574–1577 (2004). · DOI
  52. Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004). · DOI · Paper page
  53. Sashida, G. et al. Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nat. Commun. 5, 4177 (2014). · DOI
  54. Gao, Z. et al. PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes. Mol. Cell 45, 344–356 (2012). · DOI · Paper page
  55. Gearhart, M. D., Corcoran, C. M., Wamstad, J. A. & Bardwell, V. J. Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. Mol. Cell. Biol. 26, 6880–6889 (2006). · DOI · Paper page
  56. Huynh, K. D., Fischle, W., Verdin, E. & Bardwell, V. J. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev. 14, 1810–1823 (2000). · DOI · Paper page
  57. Damm, F. et al. BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders. Blood 122, 3169–3177 (2013). · DOI
  58. Scheuermann, J. C. et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465, 243–247 (2010). · DOI · Paper page
  59. Abdel-Wahab, O. et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 22, 180–193 (2012). · DOI · Paper page
  60. Balasubramani, A. et al. Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1−BAP1 complex. Nat. Commun. 6, 7307 (2015). · DOI · Paper page
  61. Cao, Q. et al. BCOR regulates myeloid cell proliferation and differentiation. Leukemia 30, 1155–1165 (2016). · DOI
  62. Thota, S. et al. Genetic alterations of the cohesin complex genes in myeloid malignancies. Blood 124, 1790–1798 (2014). · DOI
  63. Losada, A. Cohesin in cancer: chromosome segregation and beyond. Nat. Rev. Cancer 14, 389–393 (2014). · DOI
  64. Horsfield, J. A. et al. Cohesin-dependent regulation of Runx genes. Development 134, 2639–2649 (2007). · DOI
  65. Leeke, B., Marsman, J., O'Sullivan, J. M. & Horsfield, J. A. Cohesin mutations in myeloid malignancies: underlying mechanisms. Exp. Hematol. Oncol. 3, 13 (2014). · DOI
  66. Marsman, J. et al. Cohesin and CTCF differentially regulate spatiotemporal runx1 expression during zebrafish development. Biochim. Biophys. Acta 1839, 50–61 (2014). · DOI
  67. Mazumdar, C. et al. Leukemia-associated cohesin mutants dominantly enforce stem cell programs and impair human hematopoietic progenitor differentiation. Cell Stem Cell 17, 675–688 (2015). · DOI
  68. Hahn, C. N. et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat. Genet. 43, 1012–1017 (2011). · DOI · Paper page
  69. Ito, Y., Bae, S. C. & Chuang, L. S. The RUNX family: developmental regulators in cancer. Nat. Rev. Cancer 15, 81–95 (2015). · DOI · Paper page
  70. Zhang, M. Y. et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat. Genet. 47, 180–185 (2015). · DOI
  71. Owen, C. J. et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 112, 4639–4645 (2008). · DOI · Paper page
  72. Tsai, F. Y. et al. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371, 221–226 (1994). · DOI · Paper page
  73. Bejar, R. et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124, 2705–2712 (2014). · DOI
  74. Rampal, R. et al. DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Rep. 9, 1841–1855 (2014). · DOI · Paper page
  75. Wang, Y. et al. WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol. Cell 57, 662–673 (2015). · DOI
  76. Soenen, V. et al. 17p Deletion in acute myeloid leukemia and myelodysplastic syndrome. Analysis of breakpoints and deleted segments by fluorescence in situ. Blood 91, 1008–1015 (1998). · DOI
  77. Rucker, F. G. et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 119, 2114–2121 (2012). · DOI · Paper page
  78. Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004). · DOI · Paper page
  79. Kaneko, H., Misawa, S., Horiike, S., Nakai, H. & Kashima, K. TP53 mutations emerge at early phase of myelodysplastic syndrome and are associated with complex chromosomal abnormalities. Blood 85, 2189–2193 (1995). · DOI
  80. Swisher, E. M. et al. Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA Oncol. 2, 370–372 (2016). · DOI
  81. Zhao, Z. et al. p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev. 24, 1389–1402 (2010). · DOI
  82. Walter, M. J. et al. Clonal architecture of secondary acute myeloid leukemia. N. Engl. J. Med. 366, 1090–1098 (2012). · DOI
  83. Furitsu, T. et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J. Clin. Invest. 92, 1736–1744 (1993). · DOI · Paper page
  84. Kottaridis, P. D. et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98, 1752–1759 (2001). · DOI
  85. Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005). · DOI · Paper page
  86. Makishima, H. et al. Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. J. Clin. Oncol. 27, 6109–6116 (2009). · DOI
  87. Pardanani, A. D. et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108, 3472–3476 (2006). · DOI
  88. Sanada, M. et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 460, 904–908 (2009). · DOI
  89. Sargin, B. et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 110, 1004–1012 (2007). · DOI
  90. Saur, S. J., Sangkhae, V., Geddis, A. E., Kaushansky, K. & Hitchcock, I. S. Ubiquitination and degradation of the thrombopoietin receptor c-Mpl. Blood 115, 1254–1263 (2010). · DOI
  91. Javadi, M., Richmond, T. D., Huang, K. & Barber, D. L. CBL linker region and RING finger mutations lead to enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling via elevated levels of JAK2 and LYN. J. Biol. Chem. 288, 19459–19470 (2013). · DOI
  92. Haase, D. et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110, 4385–4395 (2007). · DOI
  93. Bochtler, T., Frohling, S. & Kramer, A. Role of chromosomal aberrations in clonal diversity and progression of acute myeloid leukemia. Leukemia 29, 1243–1252 (2015). · DOI
  94. Bernasconi, P. et al. Does cytogenetic evolution have any prognostic relevance in myelodysplastic syndromes? A study on 153 patients from a single institution. Ann. Hematol. 89, 545–551 (2010). · DOI
  95. Wang, H., Wang, X. Q., Xu, X. P. & Lin, G. W. Cytogenetic evolution correlates with poor prognosis in myelodysplastic syndrome. Cancer Genet. Cytogenet. 196, 159–166 (2010). · DOI
  96. Komrokji, R. S., Padron, E., Ebert, B. L. & List, A. F. Deletion 5q MDS: molecular and therapeutic implications. Best practice and research. Clin. Haematol. 26, 365–375 (2013).
  97. Van den Berghe, H. et al. Distinct haematological disorder with deletion of long arm of no. 5 chromosome. Nature 251, 437–438 (1974). · DOI
  98. Chen, T. H. et al. Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice. Blood 117, 1530–1539 (2011). · DOI
  99. Kumar, M. S. et al. Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome. Blood 118, 4666–4673 (2011). · DOI
  100. Starczynowski, D. T. et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat. Med. 16, 49–58 (2010). · DOI · Paper page
  101. Stoddart, A. et al. Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice. Blood 123, 1069–1078 (2014). · DOI
  102. Grisendi, S. et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature 437, 147–153 (2005). · DOI · Paper page
  103. Varney, M. E. et al. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J. Exp. Med. 212, 1967–1985 (2015). · DOI
  104. DeWard, A. D., Leali, K., West, R. A., Prendergast, G. C. & Alberts, A. S. Loss of RhoB expression enhances the myelodysplastic phenotype of mammalian diaphanous-related Formin mDia1 knockout mice. PLoS ONE 4, e7102 (2009). · DOI
  105. Graubert, T. A. et al. Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis. PloS ONE 4, e4583 (2009). · DOI
  106. Polprasert, C. et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27, 658–670 (2015). · DOI · Paper page
  107. Ebert, B. L. et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451, 335–339 (2008). · DOI · Paper page
  108. Barlow, J. L. et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q− syndrome. Nat. Med. 16, 59–66 (2010). · DOI
  109. Schneider, R. K. et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat. Med. 22, 288–297 (2016). · DOI
  110. Ludwig, L. S. et al. Altered translation of GATA1 in Diamond-Blackfan anemia. Nat. Med. 20, 748–753 (2014). · DOI · Paper page
  111. Vlachos, A. et al. Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q− syndrome. Blood 122, 2487–2490 (2013). · DOI
  112. Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010). · DOI · Paper page
  113. Chen, C. et al. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25, 652–665 (2014). · DOI · Paper page
  114. McNerney, M. E. et al. CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia. Blood 121, 975–983 (2013). · DOI
  115. Nikoloski, G. et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat. Genet. 42, 665–667 (2010). · DOI · Paper page
  116. Kantarjian, H. et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106, 1794–1803 (2006). · DOI · Paper page
  117. Traina, F. et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia 28, 78–87 (2014). · DOI · Paper page
  118. Jadersten, M. et al. Clonal heterogeneity in the 5q− syndrome: 53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Haematologica 94, 1762–1766 (2009). · DOI
  119. Raza, A. et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 111, 86–93 (2008). · DOI · Paper page
  120. Koreth, J. et al. Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J. Clin. Oncol. 31, 2662–2670 (2013). · DOI
  121. Della Porta, M. G. et al. Clinical effects of driver somatic mutations on the outcomes of patients with myelodysplastic syndromes treated with allogeneic hematopoietic stem-cell transplantation. J. Clin. Oncol. 30, 3627–3637 (2016). · DOI
  122. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013). · DOI · Paper page
  123. Chan, S. M. et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat. Med. 21, 178–184 (2015). · DOI · Paper page
  124. Fandy, T. E. et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood 114, 2764–2773 (2009). · DOI · Paper page
  125. Lee, S. C. et al. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat. Med. 22, 672–678 (2016). · DOI · Paper page
  126. Maxson, J. E. et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N. Engl. J. Med. 368, 1781–1790 (2013). · DOI · Paper page
  127. Meggendorfer, M. et al. SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. Leukemia 27, 1852–1860 (2013). · DOI
  128. Mason, C. C. et al. Age-related mutations and chronic myelomonocytic leukemia. Leukemia 30, 906–913 (2016). · DOI
  129. Lane, A. A. et al. Low frequency clonal mutations recoverable by deep sequencing in patients with aplastic anemia. Leukemia 27, 968–971 (2013). · DOI
  130. Shen, W. et al. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J. Clin. Invest. 124, 4529–4538 (2014). · DOI
  131. Wilson, D. B., Link, D. C., Mason, P. J. & Bessler, M. Inherited bone marrow failure syndromes in adolescents and young adults. Ann. Med. 46, 353–363 (2014). · DOI
  132. Mitchell, J. R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999). · DOI · Paper page
  133. Noetzli, L. et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat. Genet. 47, 535–538 (2015). · DOI
  134. McBride, K. A. et al. Li-Fraumeni syndrome: cancer risk assessment and clinical management. Nat. Rev. Clin. Oncol. 11, 260–271 (2014). · DOI
  135. Hsu, A. P. et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118, 2653–2655 (2011). · DOI · Paper page
  136. Ostergaard, P. et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat. Genet. 43, 929–931 (2011). · DOI · Paper page
  137. Lewinsohn, M. et al. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 127, 1017–1023 (2016). · DOI
  138. Boocock, G. R. et al. Mutations in SBDS are associated with Shwachman–Diamond syndrome. Nat. Genet. 33, 97–101 (2003). · DOI · Paper page
  139. Zhou, T., Kinney, M. C., Scott, L. M., Zinkel, S. S. & Rebel, V. I. Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research. Blood 126, 1057–1068 (2015). · DOI
  140. Li, Q. et al. Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 504, 143–147 (2013). · DOI
  141. Dolatshad, H. et al. Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. Leukemia 29, 1798 (2015). · DOI
  142. Chan, C. K. et al. Endochondral ossification is required for haematopoietic stem-cell niche formation. Nature 457, 490–494 (2009). · DOI
  143. Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012). · DOI
  144. Kode, A. et al. Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature 506, 240–244 (2014). · DOI · Paper page
  145. Schepers, K. et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell 13, 285–299 (2013). · DOI · Paper page
  146. Epperson, D. E., Nakamura, R., Saunthararajah, Y., Melenhorst, J. & Barrett, A. J. Oligoclonal T cell expansion in myelodysplastic syndrome: evidence for an autoimmune process. Leukemia Res. 25, 1075–1083 (2001). · DOI
  147. Molldrem, J. J. et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann. Intern. Med. 137, 156–163 (2002). · DOI
  148. Saunthararajah, Y., Nakamura, R., Wesley, R., Wang, Q. J. & Barrett, A. J. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood 102, 3025–3027 (2003). · DOI
  149. Sloand, E. M., Wu, C. O., Greenberg, P., Young, N. & Barrett, J. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J. Clin. Oncol. 26, 2505–2511 (2008). · DOI
  150. Patel, J. P. et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 366, 1079–1089 (2012). · DOI
  151. Boultwood, J., Dolatshad, H., Varanasi, S. S., Yip, B. H. & Pellagatti, A. The role of splicing factor mutations in the pathogenesis of the myelodysplastic syndromes. Adv. Biol. Regul. 54, 153–161 (2014). · DOI
  152. Fenaux, P. et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 118, 3765–3776 (2011). · DOI
  153. Cordoba, I. et al. Better prognosis for patients with del(7q) than for patients with monosomy 7 in myelodysplastic syndrome. Cancer 118, 127–133 (2012). · DOI
  154. Bacher, U. et al. Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact. Br. J. Haematol. 164, 822–833 (2014). · DOI
  155. Wang, S. A. et al. Myelodysplastic syndromes with deletions of chromosome 11q lack cryptic MLL rearrangement and exhibit characteristic clinicopathologic features. Leuk. Res. 35, 351–357 (2011). · DOI
  156. Wong, A. K. et al. Loss of the Y chromosome: an age-related or clonal phenomenon in acute myelogenous leukemia/myelodysplastic syndrome? Arch. Pathol. Lab. Med. 132, 1329–1332 (2008). · DOI

Cited by

See all 678

Metadata

Authors
Sperling, A. S., Gibson, C. J., & Ebert, B. L.
Venue
Nature Reviews Cancer
Publisher
Springer Science and Business Media LLC
Published
2016-11-11
Volume
17
Issue
1
Pages
5-19
ISSN
  • 1474-175X (ISSN-L)
  • 1474-1768
DOI
10.1038/nrc.2016.112
OpenAlex
W2551607099
Cited by
678
References
45
FWCI
14.02
Type
journal article
Language
en
Open access
green
Licence
www.springer.com/tdm (tdm)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. https://app.cochat.ai/papers/10.1038/nrc.2016.112
The paper
Sperling, A. S., Gibson, C. J., & Ebert, B. L. (2017). The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nature Reviews Cancer. https://doi.org/10.1038/nrc.2016.112

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.