Review Article | Published:

Therapy-related myeloid neoplasms: when genetics and environment collide

Nature Reviews Cancer volume 17, pages 513527 (2017) | Download Citation

Abstract

Therapy-related myeloid neoplasms (t-MN) arise as a late effect of chemotherapy and/or radiation administered for a primary condition, typically a malignant disease, solid organ transplant or autoimmune disease. Survival is measured in months, not years, making t-MN one of the most aggressive and lethal cancers. In this Review, we discuss recent developments that reframe our understanding of the genetic and environmental aetiology of t-MN. Emerging data are illuminating who is at highest risk of developing t-MN, why t-MN are chemoresistant and how we may use this information to treat and ultimately prevent this lethal disease.

Key points

  • Therapy-related myeloid neoplasms (t-MN) arise as a late effect of chemotherapy and/or radiation administered for a primary condition, often a malignant disease, solid organ transplant or autoimmune disease.

  • The majority of t-MN have high-risk cytogenetic features, and the prognosis for patients with t-MN is poor, with a 5-year survival of 10%.

  • Germline mutations in genes associated with an inherited predisposition to cancer have been identified in approximately 20% of patients with t-MN.

  • Chemotherapy and/or radiotherapy promotes clonal selection of pre-existing, mutant haematopoietic stem cells in addition to directly inducing leukaemogenic mutations.

  • The somatic mutations in t-MN are indistinguishable from those occurring in de novo acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS).

  • Large chromosomal deletions, such as del(5q) and del(7q), that occur in t-MN do not harbour a single, recessive tumour suppressor gene but instead are part of a contiguous gene syndrome (CGS). Moreover, the genes involved in CGSs on these chromosomes act by haploinsufficiency.

  • An aberrant bone marrow microenvironment directly contributes to the pathogenesis of t-MN.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant. Am. J. Clin. Patholol. 127, 197–205 (2007).

  2. 2.

    , , & Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–47 (2016).

  3. 3.

    et al. Germline variants in targeted tumor sequencing using matched normal DNA. JAMA Oncology 2, 104–111 (2016).

  4. 4.

    et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375, 443–453 (2016).

  5. 5.

    et al. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336–2346 (2015).

  6. 6.

    et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518, 552–555 (2015).Largest study of somatic mutations in t-MN that also reported pre-existing TP53 mutations prior to t-MN development.

  7. 7.

    et al. Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases. Leuk. Res. 39, 348–354 (2015).

  8. 8.

    et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125, 1367–1376 (2015).

  9. 9.

    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).First in vivo evidence of t-MN as a CGS on chromosome arm 5q.

  10. 10.

    et al. CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia. Blood 121, 975–983 (2013).

  11. 11.

    et al. Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis. eLife (2015).

  12. 12.

    Myelodysplastic syndromes: revisiting the role of the bone marrow microenvironment in disease pathogenesis. Int. J. Hematol. 95, 17–25 (2012).

  13. 13.

    & Influence of bone marrow microenvironment on leukemic stem cells: breaking up an intimate relationship. Adv. Cancer Res. 127, 227–252 (2015).

  14. 14.

    & Regulation of hematopoietic stem cells by bone marrow stromal cells. Trends Immunol. 35, 32–37 (2014).

  15. 15.

    & Myeloid malignancies and the microenvironment. Blood 129, 811–822 (2016).

  16. 16.

    et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol. Biomarkers Prev. 22, 561–570 (2013).

  17. 17.

    & Cancer survivorship issues: life after treatment & implications for an aging population. Clin. J. Oncol. 32, 2662–2668 (2014).

  18. 18.

    et al. Incidence of myelodysplastic syndromes within a nonprofit healthcare system in western Washington state, 2005–2006. Am. J. Hematol. 85, 765–770 (2010).

  19. 19.

    et al. Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting: a report from the Swedish Acute Leukemia Registry. Am. J. Hematol. 90, 208–214 (2015).

  20. 20.

    et al. Characteristics and outcome of therapy-related myeloid neoplasms: report from the Italian network on secondary leukemias. Am. J. Hematol. 90, E80–E85 (2015).

  21. 21.

    et al. Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975–2008. Blood 121, 2996–3004 (2013).

  22. 22.

    et al. Risk of myeloid neoplasms after solid organ transplantation. Leukemia 28, 2317–2323 (2014).

  23. 23.

    et al. Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation. Leukemia 30, 285–294 (2016).Provides a thorough analysis of environmental risk factors for t-MN.

  24. 24.

    et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102, 43–52 (2003).

  25. 25.

    et al. Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience. J. Clin. Oncol. 33, 340–348 (2015).

  26. 26.

    et al. Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood 123, 1658–1664 (2014).

  27. 27.

    et al. Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients. J. Clin. Oncol. 21, 897–906 (2003).

  28. 28.

    et al. Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997. Blood 118, 3525–3527 (2011).

  29. 29.

    et al. Characteristics and outcomes of patients with multiple myeloma who develop therapy-related myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia. Clin. Lymphoma Myeloma Leuk. 15, 110–114 (2015).

  30. 30.

    et al. Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: a report from the Children's Oncology Group. Blood 109, 46–51 (2007).

  31. 31.

    et al. Monogenic and polygenic determinants of sarcoma risk: an international genetic study. Lancet Oncol. 17, 1261–1271 (2016).

  32. 32.

    Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors. Cancer 121, 648–663 (2015).

  33. 33.

    et al. Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia. Cancer 122, 304–311 (2016).This study demonstrates a high frequency of mutations in cancer predisposition genes in patients who developed t-MN following treatment for breast cancer.

  34. 34.

    et al. Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms. J. Med. Genet. 49, 422–428 (2012).

  35. 35.

    et al. Fanconi anemia gene variants in therapy-related myeloid neoplasms. Blood Cancer J. 5, e323 (2015).

  36. 36.

    et al. The p53 gene in pediatric therapy-related leukemia and myelodysplasia. Blood 87, 4376–4381 (1996).

  37. 37.

    et al. Association of germline p53 mutation with MLL segmental jumping translocation in treatment-related leukemia. Blood 91, 4451–4456 (1998).

  38. 38.

    et al. Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML. JAMA 305, 1568–1576 (2011).

  39. 39.

    et al. Acute lymphoblastic leukemia after temozolomide treatment for anaplastic astrocytoma in a child with a germline TP53 mutation. Pediatr. Blood Cancer 55, 577–579 (2010).

  40. 40.

    et al. Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice. Blood 127, 310–313 (2016).

  41. 41.

    et al. Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours. Genes Chromosomes Cancer 25, 91–96 (1999).

  42. 42.

    & Is TP53 dysfunction required for BRCA1-associated carcinogenesis? Mol. Cell. Endocrinol. 155, 143–152 (1999).

  43. 43.

    et al. The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia. Leukemia 28, 1242–1251 (2014).

  44. 44.

    et al. Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. Cancer 79, 1438–1446 (1997).

  45. 45.

    et al. Therapy-induced malignant neoplasms in Nf1 mutant mice. Cancer Cell 8, 337–348 (2005).

  46. 46.

    et al. Genetically mediated Nf1 loss in mice promotes diverse radiation-induced tumors modeling second malignant neoplasms. Cancer Res. 72, 6425–6434 (2012).

  47. 47.

    et al. Melphalan may be a more potent leukemogen than cyclophosphamide. Ann. Intern. Med. 105, 360–367 (1986).

  48. 48.

    et al. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N. Engl. J. Med. 326, 1745–1751 (1992).

  49. 49.

    et al. Risk of leukemia after platinum-based chemotherapy for ovarian cancer. N. Engl. J. Med. 340, 351–357 (1999).

  50. 50.

    et al. Treatment-associated leukemia following testicular cancer. J. Natl Cancer Inst. 92, 1165–1171 (2000).

  51. 51.

    The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

  52. 52.

    et al. Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation. Blood 104, 822–828 (2004).

  53. 53.

    et al. Fludarabine as a risk factor for poor stem cell harvest, treatment-related MDS and AML in follicular lymphoma patients after autologous hematopoietic cell transplantation. Bone Marrow Transplant. 47, 488–493 (2012).

  54. 54.

    et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin. Cancer Res. 21, 4257–4261 (2015).

  55. 55.

    , & Leukemia in atomic bomb survivors. I. General observations. Blood 9, 574–585 (1954).

  56. 56.

    et al. Second malignant neoplasms and cardiovascular disease following radiotherapy. J. Natl Cancer Inst. 104, 357–370 (2012).

  57. 57.

    et al. Acute myeloid leukemia and myelodysplastic syndromes after radiation therapy are similar to de novo disease and differ from other therapy-related myeloid neoplasms. J. Clin. Oncol. 30, 2340–2347 (2012).

  58. 58.

    et al. Risk for developing myelodysplastic syndromes in prostate cancer patients definitively treated with radiation. J. Natl. Cancer Inst. 106, djt462 (2014).

  59. 59.

    et al. Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome. Cancer 117, 1463–1469 (2011).

  60. 60.

    et al. Age and acute myeloid leukemia. Blood 107, 3481–3485 (2006).

  61. 61.

    et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat. Genet. 42, 722–726 (2010).

  62. 62.

    et al. Transcript map and comparative analysis of the 1.5-Mb commonly deleted segment of human 5q31 in malignant myeloid diseases with a del(5q). Genomics 71, 235–245 (2001).

  63. 63.

    et al. Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. Proc. Natl Acad. Sci. USA 90, 5484–5488 (1993).

  64. 64.

    et al. Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases. Blood 88, 1930–1935 (1996).

  65. 65.

    et al. Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome. Blood 99, 4638–4641 (2002).

  66. 66.

    et al. Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited. J. Clin. Oncol. 30, 1343–1349 (2012).

  67. 67.

    , , , & Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood 115, 3481–3488 (2010).

  68. 68.

    et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451, 335–339 (2008).

  69. 69.

    et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat. Med. 16, 49–58 (2010).

  70. 70.

    et al. The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell 2, 380–391 (2008).

  71. 71.

    et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell 26, 509–520 (2014).

  72. 72.

    et al. Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome. Blood 118, 4666–4673 (2011).

  73. 73.

    , , , & Haploinsufficient loss of multiple 5q genes may fine-tune Wnt signaling in del(5q) therapy-related myeloid neoplasms. Blood 126, 2899–2901 (2015).

  74. 74.

    Contiguous gene syndromes: a component of recognizable syndromes. J. Pediatr. 109, 231–241 (1986).

  75. 75.

    et al. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. Nature 531, 471–475 (2016).Demonstration of a CGS on chromosome arm 17p.

  76. 76.

    et al. 13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia. Leukemia 25, 489–497 (2011).

  77. 77.

    et al. PVT1 dependence in cancer with MYC copy-number increase. Nature 512, 82–86 (2014).

  78. 78.

    et al. Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science 337, 104–109 (2012).

  79. 79.

    et al. Inactivating CUX1 mutations promote tumorigenesis. Nat. Genet. 46, 33–38 (2014).

  80. 80.

    et al. Recurrent genetic defects on chromosome 7q in myeloid neoplasms. Leukemia 28, 1348–1351 (2014).

  81. 81.

    et al. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25, 652–665 (2014).

  82. 82.

    et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell 24, 305–317 (2013).

  83. 83.

    et al. Ataxia-pancytopenia syndrome Is caused by missense mutations in SAMD9L. Am. J. Hum. Genet. 98, 1146–1158 (2016).

  84. 84.

    et al. The isochromosome i(7)(q10) carrying c.258 + 2t>c mutation of the SBDS gene does not promote development of myeloid malignancies in patients with Shwachman syndrome. Leukemia 23, 708–711 (2009).

  85. 85.

    et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat. Genet. 48, 792–797 (2016).

  86. 86.

    et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

  87. 87.

    et al. The spectrum of somatic mutations in high-risk acute myeloid leukaemia with −7/del(7q). Br. J. Haematol. 166, 550–556 (2014).

  88. 88.

    et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 66, 3987–3991 (2006).

  89. 89.

    et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N. Engl. J. Med. 352, 1529–1538 (2005).

  90. 90.

    , , & DNA damage induced by alkylating agents and repair pathways. J. Nucleic Acids 2010, 543531 (2010).

  91. 91.

    et al. TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. J. Hematol. Oncol. 8, 45 (2015).

  92. 92.

    , & Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia & acute myeloid leukemia after exposure to alkylating agents & significantly associated with deletion or loss of 5q, a complex karyotype and a poor prognosis. J. Clin. Oncol. 19, 1405–1413 (2001).

  93. 93.

    et al. RAS, FLT3, and TP53 mutations in therapy-related myeloid malignancies with abnormalities of chromosomes 5 and 7. Genes Chromosomes Cancer 39, 217–223 (2004).

  94. 94.

    , , , & Drugging the undruggable RAS: mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014).

  95. 95.

    et al. Preexisting TP53 mutation in therapy-related acute myeloid leukemia. Ann. Hematol. 94, 527–529 (2015).

  96. 96.

    et al. The complete mutatome and clonal architecture of del(5q) [Abstract 608]. (American Society of Hematology Annual Meeting, 2015).

  97. 97.

    et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell 25, 794–808 (2014).

  98. 98.

    et al. Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia. Blood 125, 706–709 (2015).

  99. 99.

    et al. Clonal haemopoiesis following cytotoxic therapy for lymphoma. Leukemia 7, 795–800 (1993).

  100. 100.

    et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 493, 406–410 (2013).

  101. 101.

    et al. Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA Oncology 2, 370–372 (2016).

  102. 102.

    et al. PPM1D mosaic truncating variants in ovarian cancer cases may be treatment-related somatic mutations. J. Natl. Cancer Inst. 108, djv347 (2016).

  103. 103.

    et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126, 9–16 (2015).

  104. 104.

    et al. Mosaic uniparental disomies and aneuploidies as large structural variants of the human genome. Am. J. Hum. Genet. 87, 129–138 (2010).

  105. 105.

    et al. Age-related somatic structural changes in the nuclear genome of human blood cells. Am. J. Hum. Genet. 90, 217–228 (2012).

  106. 106.

    et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44, 651–658 (2012).

  107. 107.

    et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44, 642–650 (2012).

  108. 108.

    et al. Characterization of large structural genetic mosaicism in human autosomes. Am. J. Hum. Genet. 96, 487–497 (2015).

  109. 109.

    et al. Confirmation of the reported association of clonal chromosomal mosaicism with an increased risk of incident hematologic cancer. PLoS ONE 8, e59823 (2013).

  110. 110.

    et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

  111. 111.

    et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

  112. 112.

    et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).

  113. 113.

    et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep. 10, 1239–1245 (2015).

  114. 114.

    , , & Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016).

  115. 115.

    et al. Less is more: unveiling the functional core of hematopoietic stem cells through knockout mice. Cell Stem Cell 11, 302–317 (2012).

  116. 116.

    et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011).

  117. 117.

    et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2012).

  118. 118.

    et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).

  119. 119.

    & p53-mediated hematopoietic stem and progenitor cell competition. Cell Stem Cell 6, 309–322 (2010).

  120. 120.

    et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 18, 100–111 (2017).

  121. 121.

    et al. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 18, 112–121 (2017).

  122. 122.

    et al. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J. Clin. Oncol. 35, 1598–1605 (2017).References 120–122 demonstrate CHIP as a potential biomarker for t-MN.

  123. 123.

    et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N. Engl. J. Med. 373, 35–47 (2015).

  124. 124.

    et al. Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia. Cancer Genet. 208, 115–128 (2015).

  125. 125.

    , , , & Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood 99, 3129–3135 (2002).

  126. 126.

    & Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell 16, 239–253 (2015).

  127. 127.

    et al. Mesenchymal stromal cells from patients with myelodyplastic syndrome display distinct functional alterations that are modulated by lenalidomide. Haematologica 98, 1677–1685 (2013).

  128. 128.

    et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell 14, 824–837 (2014).This study showed that patient-derived MSCs promote MDS stem cell growth in mouse xenografts.

  129. 129.

    et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852–857 (2010).

  130. 130.

    et al. Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc. Blood 123, 228–238 (2014).

  131. 131.

    et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell 2, 274–283 (2008).

  132. 132.

    et al. The Wnt/β-catenin pathway is required for the development of leukemia stem cells in AML. Science 327, 1650–1653 (2010).

  133. 133.

    et al. The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood 115, 3489–3497 (2010).

  134. 134.

    et al. Impairment of PI3K/AKT and WNT/β-catenin pathways in bone marrow mesenchymal stem cells isolated from patients with myelodysplastic syndromes. Exp. Hematol. 44, 75–83e71-74 (2016).

  135. 135.

    et al. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506, 240–244 (2014).

  136. 136.

    et al. Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell 19, 613–627 (2016).

  137. 137.

    & 'CHIP'ping away at clonal hematopoiesis. Leukemia 30, 1633–1635 (2016).

  138. 138.

    et al. Epidemiology and clinical significance of secondary and therapy-related acute myeloid leukemia: a national population-based cohort study. J. Clin. Oncol. 33, 3641–3649 (2015).

  139. 139.

    et al. Survival is poorer in patients with secondary core-binding factor acute myelogenous leukemia compared with de novo core-binding factor leukemia. Cancer 115, 3217–3221 (2009).

  140. 140.

    et al. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood 117, 2137–2145 (2011).

  141. 141.

    et al. Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 51, 771–777 (2016).

  142. 142.

    et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J. Clin. Oncol. 32, 2691–2698 (2014).

  143. 143.

    et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N. Engl. J. Med. 375, 2023–2036 (2016).

  144. 144.

    et al. Detection of clonal and subclonal copy-number variants in cell-free DNA from patients with breast cancer using a massively multiplexed PCR methodology. Transl Oncol. 8, 407–416 (2015).

  145. 145.

    et al. Identifying inherited and acquired genetic factors involved in poor stem cell mobilization and donor-derived malignancy. Biol. Blood Marrow Transplant. 22, 2100–2103 (2016).

  146. 146.

    The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 16, 1896–1905 (2002).

  147. 147.

    & Stem cells and healthy aging. Science 350, 1199–1204 (2015).

  148. 148.

    et al. Acute DNA damage activates the tumour suppressor p53 to promote radiation-induced lymphoma. Nat. Communications 6, 8477 (2015).

  149. 149.

    . Gene deletion: a new target for cancer chemotherapy. Lancet 342, 662–664 (1993).

  150. 150.

    et al. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. J. Exp. Med. 211, 605–612 (2014).

  151. 151.

    et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015).This study demonstrates that a CGS can provide a therapeutic targeting opportunity.

  152. 152.

    , & Somatic mosaicism: on the road to cancer. Nat. Rev. Cancer 16, 43–55 (2016).

  153. 153.

    et al. Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia. Haematologica 98, 908–912 (2013).

  154. 154.

    , , & Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 19, 2232–2240 (2005).

  155. 155.

    et al. Mutations of epigenetic regulators and of the spliceosome machinery in therapy-related myeloid neoplasms and in acute leukemias evolved from chronic myeloproliferative diseases. Leukemia 27, 982–985 (2013).

  156. 156.

    , , & Activating mutations of JAK2V617F are uncommon in t-MDS and t-AML and are only observed in atypic cases. Leukemia 20, 547–548 (2006).

  157. 157.

    , , , & A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia. Haematologica 92, 744–752 (2007).

  158. 158.

    , , & NPM1 mutations in therapy-related acute myeloid leukemia with uncharacteristic features. Leukemia 22, 951–955 (2008).

  159. 159.

    , , & Mutations of the PTPN11 gene in therapy-related MDS and AML with rare balanced chromosome translocations. Genes Chromosomes Cancer 46, 517–521 (2007).

  160. 160.

    , & Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation. Blood 104, 1474–1481 (2004).

  161. 161.

    et al. SETBP1 mutations in 106 patients with therapy-related myeloid neoplasms. Haematologica 99, e152–e153 (2014).

  162. 162.

    et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98, 1312–1320 (2001).

  163. 163.

    et al. Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B. Blood 108, 3280–3288 (2006).

  164. 164.

    et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116, 354–365 (2010).

  165. 165.

    et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood 116, 4086–4094 (2010).

  166. 166.

    et al. Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia. Oncogene 24, 4129–4137 (2005).

  167. 167.

    et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 100, 59–66 (2002).

  168. 168.

    et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J. Clin. Oncol. 28, 3636–3643 (2010).

  169. 169.

    et al. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 106, 3377–3379 (2005).

  170. 170.

    et al. Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia. Genes Chromosomes Cancer 37, 237–251 (2003).

  171. 171.

    et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N. Engl. J. Med. 352, 254–266 (2005).

  172. 172.

    , , , & Implications of NRAS mutations in AML: a study of 2502 patients. Blood 107, 3847–3853 (2006).

  173. 173.

    et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia 25, 130–134 (2011).

  174. 174.

    et al. Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. Blood 123, 914–920 (2014).

  175. 175.

    et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J. Clin. Oncol. 29, 1364–1372 (2011).

  176. 176.

    et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 114, 5352–5361 (2009).

  177. 177.

    et al. SETBP1 mutation analysis in 944 patients with MDS and AML. Leukemia 27, 2072–2075 (2013).

  178. 178.

    et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med. 365, 1384–1395 (2011).

  179. 179.

    et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 118, 3803–3810 (2011).

  180. 180.

    et al. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia 26, 934–942 (2012).

  181. 181.

    et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. Blood 120, 2963–2972 (2012).

  182. 182.

    et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 366, 1079–1089 (2012).

  183. 183.

    et al. DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood 119, 559–568 (2012).

  184. 184.

    et al. Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders. Blood 92, 4031–4035 (1998).

  185. 185.

    et al. Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis. Blood 119, 6109–6117 (2012).

  186. 186.

    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).

  187. 187.

    et al. Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders. Blood 110, 719–726 (2007).

  188. 188.

    et al. Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts. Haematologica 99, 1032–1040 (2014).

  189. 189.

    et al. Knockdown of Hspa9, a del(5q31.2) gene, results in a decrease in hematopoietic progenitors in mice. Blood 117, 1530–1539 (2011).

  190. 190.

    et al. Myeloproliferative defects following targeting of the Drf1 gene encoding the mammalian diaphanous related formin mDia1. Cancer Res. 67, 7565–7571 (2007).

  191. 191.

    et al. Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat. Genet. 47, 539–543 (2015).

  192. 192.

    et al. Recurrent CDC25C mutations drive malignant transformation in FPD/AML. Nat. Communications 5, 4770 (2014).

  193. 193.

    et al. Chromosome 5q deletion and epigenetic suppression of the gene encoding α-catenin (CTNNA1) in myeloid cell transformation. Nat. Med. 13, 78–83 (2007).

  194. 194.

    et al. Common deleted genes in the 5q- syndrome: thrombocytopenia and reduced erythroid colony formation in SPARC null mice. Leukemia 21, 1931–1936 (2007).

  195. 195.

    et al. Loss of MLL5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation. Blood 113, 1432–1443 (2009).

  196. 196.

    et al. Impaired function of primitive hematopoietic cells in mice lacking the Mixed-Lineage-Leukemia homolog MLL5. Blood 113, 1444–1454 (2009).

  197. 197.

    et al. MLL5 contributes to hematopoietic stem cell fitness and homeostasis. Blood 113, 1455–1463 (2009).

  198. 198.

    et al. Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes. Proc. Natl Acad. Sci. USA 112, E6359–E6368 (2015).

  199. 199.

    et al. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. J. Exp. Med. 210, 2627–2639 (2013).

  200. 200.

    et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).

  201. 201.

    et al. Exome sequencing of familial MDS reveals novel mutations and high rates of false positive mutations in MLL3 due to pseudogene effects (Abstract #4591). (American Society of Hematology Annual Meeting, 2015).

Download references

Acknowledgements

The authors thank Angela Stoddart and Kevin M. Shannon for critical reading of the manuscript. M.E.M. is supported by NIH 1K08CA181254, The V Foundation for Cancer Research (V Foundation Scholar Award), the University of Chicago Medicine Comprehensive Cancer Center CCSG (P30 CA14599), an Institutional Research Grant (IRG-58-004-53-IRG) from the American Cancer Society and the University of Chicago Cancer Research Foundation Auxiliary Board. L.A.G. is supported by grants from the Edward P. Evans Foundation, the Taub Foundation, the Leukemia and Lymphoma Society and the Cancer Research Foundation. M.M.L. is supported by grants from NIH (CA190372) and the Edward P. Evans Foundation.

Author information

Affiliations

  1. Department of Pathology and the Department of Pediatrics, The University of Chicago, Chicago, Illinois 60637, USA.

    • Megan E. McNerney
  2. Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.

    • Lucy A. Godley
    •  & Michelle M. Le Beau
  3. University of Chicago Medicine Comprehensive Cancer Center, Chicago, Illinois 60637, USA.

    • Megan E. McNerney
    • , Lucy A. Godley
    •  & Michelle M. Le Beau

Authors

  1. Search for Megan E. McNerney in:

  2. Search for Lucy A. Godley in:

  3. Search for Michelle M. Le Beau in:

Contributions

M.E.M., L.A.G. and M.M.L. conceived of, wrote and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michelle M. Le Beau.

Glossary

Acute myeloid leukaemia

(AML). A cancer of the myeloid lineage of haematopoietic cells associated with an expansion of immature cells (≥20% blasts) and defective differentiation into the mature myeloid lineages.

Myelodysplastic syndrome

(MDS). A group of clonal disorders with dysfunctional and dysplastic haematopoiesis of one or more myeloid lineage(s) leading to decreased maturation of normal myeloid cells with <20% blasts and a risk of leukaemic transformation.

Myelodysplastic/myeloproliferative neoplasms

(MDS/MPN). Clonal haematopoietic malignancy with features of MDS and excess production of one or more myeloid lineages.

Contiguous gene syndrome

(CGS). Genetic disorder caused by chromosomal copy number change, leading to combined dosage imbalance of multiple neighbouring genes typically on the scale of <5 Mb.

Standardized incidence ratio

(SIR). The ratio of the observed-to-expected number of cases based on demographic-specific incidence rates of acute myeloid leukaemia (AML) among the general population.

Fanconi anaemia

A bone marrow failure syndrome associated with an inherited mutation in one of at least 17 specific genes associated with the DNA damage response or DNA repair.

De novo AML

Acute myeloid leukaemia (AML) arising without a prior history of exposure to cytotoxic therapies or pre-existing myeloid neoplasm.

Brachytherapy

The use of radioactive sources implanted into the tumour tissue.

Knudson's two-hit hypothesis

A model stating that tumour suppressor genes are recessive and that inactivation of both alleles is required for a malignant phenotype.

5q– syndrome

A subset of MDS with an interstitial deletion of 5q as the sole cytogenetic abnormality (or with one additional abnormality). These patients present with macrocytic anaemia, megakaryocytic dysplasia and preserved or elevated platelet counts; additionally, they have a relatively favourable prognosis.

Ataxia-pancytopenia syndrome

Also known as myelocerebellar disorder; associated with ataxia, bone marrow failure and a predisposition to myeloid leukaemia with monosomy 7.

Revertant mosaicism

When a disease-causing mutation is spontaneously somatically corrected for and the corrected cell clonally expands.

Shwachman–Diamond syndrome

An inherited disorder associated with skeletal abnormalities, exocrine pancreatic insufficiency and bone marrow failure that may progress to myeloid leukaemia with chromosome 7 abnormalities.

Transition-type mutations

A DNA mutation that changes a purine to a different purine nucleotide or a pyrimidine to a different pyrimidine.

Aplastic anaemia

A disorder characterized by pancytopenia that confers risk of transformation to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) and occurs as a result of either germline mutations or acquired immune destruction of haematopoietic precursors.

Performance status

Measure of physical functioning of the patient to help predict prognosis.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrc.2017.60

Further reading