Human leukemias are liquid malignancies characterized by diffuse infiltration of the bone marrow by transformed hematopoietic progenitors. The accessibility of tumor cells obtained from peripheral blood or through bone marrow aspirates, together with recent advances in cancer genomics and single-cell molecular analysis, have facilitated the study of clonal populations and their genetic and epigenetic evolution over time with unprecedented detail. The results of these analyses challenge the classic view of leukemia as a clonal homogeneous diffuse tumor and introduce a more complex and dynamic scenario. In this review, we present current concepts on the role of clonal evolution in lymphoid and myeloid leukemia as a driver of tumor initiation, disease progression and relapse. We also discuss the implications of these concepts in our understanding of the evolutionary mechanisms involved in leukemia transformation and therapy resistance.
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Nowell, P.C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).
Merlo, L.M., Pepper, J.W., Reid, B.J. & Maley, C.C. Cancer as an evolutionary and ecological process. Nat. Rev. Cancer 6, 924–935 (2006).
Burrell, R.A., McGranahan, N., Bartek, J. & Swanton, C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 501, 338–345 (2013).
Greaves, M. Evolutionary determinants of cancer. Cancer Discov. 5, 806–820 (2015).
Puente, X.S. & López-Otín, C. The evolutionary biography of chronic lymphocytic leukemia. Nat. Genet. 45, 229–231 (2013).
Landau, D.A., Carter, S.L., Getz, G. & Wu, C.J. Clonal evolution in hematological malignancies and therapeutic implications. Leukemia 28, 34–43 (2014).
Greaves, M. Leukaemia 'firsts' in cancer research and treatment. Nat. Rev. Cancer 16, 163–172 (2016).
Dick, J.E. Stem cell concepts renew cancer research. Blood 112, 4793–4807 (2008).
Jan, M. & Majeti, R. Clonal evolution of acute leukemia genomes. Oncogene 32, 135–140 (2013).
Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).
Song, W.J. et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat. Genet. 23, 166–175 (1999).
Smith, M.L., Cavenagh, J.D., Lister, T.A. & Fitzgibbon, J. Mutation of CEBPA in familial acute myeloid leukemia. N. Engl. J. Med. 351, 2403–2407 (2004).
Hahn, C.N. et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat. Genet. 43, 1012–1017 (2011).
Noris, P. et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood 122, 1987–1989 (2013).
Polprasert, C. et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27, 658–670 (2015).
Shah, S. et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat. Genet. 45, 1226–1231 (2013).
Zhang, M.Y. et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat. Genet. 47, 180–185 (2015).
Moriyama, T. et al. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol. 16, 1659–1666 (2015).
Greaves, M.F., Maia, A.T., Wiemels, J.L. & Ford, A.M. Leukemia in twins: lessons in natural history. Blood 102, 2321–2333 (2003).
Sanjuan-Pla, A. et al. Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia. Blood 126, 2676–2685 (2015).
Hong, D. et al. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 319, 336–339 (2008).
Greaves, M. Infection, immune responses and the aetiology of childhood leukaemia. Nat. Rev. Cancer 6, 193–203 (2006).
Jacobs, K.B. et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44, 651–658 (2012).
Laurie, C.C. et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44, 642–650 (2012).
Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).
Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).
Busque, L. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Genet. 44, 1179–1181 (2012).
Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356–361 (2011).
Li, A.H., Rosenquist, R., Forestier, E., Lindh, J. & Roos, G. Detailed clonality analysis of relapsing precursor B acute lymphoblastic leukemia: implications for minimal residual disease detection. Leuk. Res. 25, 1033–1045 (2001).
de Haas, V. et al. Quantification of minimal residual disease in children with oligoclonal B-precursor acute lymphoblastic leukemia indicates that the clones that grow out during relapse already have the slowest rate of reduction during induction therapy. Leukemia 15, 134–140 (2001).
Notta, F. et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362–367 (2011).
Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012).
Jan, M. et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci. Transl. Med. 4, 149ra118 (2012).
Paguirigan, A.L. et al. Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia. Sci. Transl. Med. 7, 281re2 (2015).
Puente, X.S. et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature 526, 519–524 (2015).
Landau, D.A. et al. Mutations driving CLL and their evolution in progression and relapse. Nature 526, 525–530 (2015).
Makishima, H. et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat. Genet. 49, 204–212 (2017).
Mossner, M. et al. Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure. Blood 128, 1246–1259 (2016).
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).
Shlush, L.I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).
Damm, F. et al. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discov. 4, 1088–1101 (2014).
Kikushige, Y. et al. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell 20, 246–259 (2011).
Chung, S.S. et al. Hematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia. Sci. Transl. Med. 6, 238ra71 (2014).
Sperling, A.S., Gibson, C.J. & Ebert, B.L. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat. Rev. Cancer 17, 5–19 (2017).
Walter, M.J. et al. Clonal architecture of secondary acute myeloid leukemia. N. Engl. J. Med. 366, 1090–1098 (2012).
Green, M.R. et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc. Natl. Acad. Sci. USA 112, E1116–E1125 (2015).
Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).
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).
Horiike, S. et al. Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype. Leukemia 13, 1235–1242 (1999).
Side, L.E. et al. RAS, FLT3, and TP53 mutations in therapy-related myeloid malignancies with abnormalities of chromosomes 5 and 7. Genes Chromosom. Cancer 39, 217–223 (2004).
Wong, T.N. et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518, 552–555 (2015).
Takahashi, K. et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 18, 100–111 (2017).
Gibson, C.J. et al. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J. Clin. Oncol. 35, 1598–1605 (2017).
Young, N.S., Calado, R.T. & Scheinberg, P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood 108, 2509–2519 (2006).
Socié, G., Rosenfeld, S., Frickhofen, N., Gluckman, E. & Tichelli, A. Late clonal diseases of treated aplastic anemia. Semin. Hematol. 37, 91–101 (2000).
Yoshizato, T. et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N. Engl. J. Med. 373, 35–47 (2015).
Maciejewski, J.P., Risitano, A., Sloand, E.M., Nunez, O. & Young, N.S. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood 99, 3129–3135 (2002).
Dumitriu, B. et al. Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia. Blood 125, 706–709 (2015).
Katagiri, T. et al. Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia. Blood 118, 6601–6609 (2011).
Afable, M.G. II et al. SNP array-based karyotyping: differences and similarities between aplastic anemia and hypocellular myelodysplastic syndromes. Blood 117, 6876–6884 (2011).
Hillmen, P., Lewis, S.M., Bessler, M., Luzzatto, L. & Dacie, J.V. Natural history of paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 333, 1253–1258 (1995).
Ogawa, S. Clonal hematopoiesis in acquired aplastic anemia. Blood 128, 337–347 (2016).
Quentin, S. et al. Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions. Blood 117, e161–e170 (2011).
Horwitz, M., Benson, K.F., Person, R.E., Aprikyan, A.G. & Dale, D.C. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat. Genet. 23, 433–436 (1999).
Klein, C. et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat. Genet. 39, 86–92 (2007).
Devriendt, K. et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat. Genet. 27, 313–317 (2001).
Bonilla, M.A. et al. Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. N. Engl. J. Med. 320, 1574–1580 (1989).
Rosenberg, P.S. et al. Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br. J. Haematol. 150, 196–199 (2010).
Germeshausen, M., Ballmaier, M. & Welte, K. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey. Blood 109, 93–99 (2007).
Skokowa, J. et al. Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood 123, 2229–2237 (2014).
Papaemmanuil, E. et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616–3627, quiz 3699 (2013).
Ortmann, C.A. et al. Effect of mutation order on myeloproliferative neoplasms. N. Engl. J. Med. 372, 601–612 (2015).
Cortés, J.R. & Palomero, T. The curious origins of angioimmunoblastic T-cell lymphoma. Curr. Opin. Hematol. 23, 434–443 (2016).
Shaknovich, R., De, S. & Michor, F. Epigenetic diversity in hematopoietic neoplasms. Biochim. Biophys. Acta 1846, 477–484 (2014).
Guièze, R. & Wu, C.J. Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia. Blood 126, 445–453 (2015).
Li, S., Mason, C.E. & Melnick, A. Genetic and epigenetic heterogeneity in acute myeloid leukemia. Curr. Opin. Genet. Dev. 36, 100–106 (2016).
Kulis, M. et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat. Genet. 44, 1236–1242 (2012).
Figueroa, M.E. et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17, 13–27 (2010).
Milani, L. et al. DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia. Blood 115, 1214–1225 (2010).
Geng, H. et al. Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. Cancer Discov. 2, 1004–1023 (2012).
Li, S. et al. Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat. Med. 22, 792–799 (2016).
Pan, H. et al. Epigenomic evolution in diffuse large B-cell lymphomas. Nat. Commun. 6, 6921 (2015).
Sandoval, J. et al. Genome-wide DNA methylation profiling predicts relapse in childhood B-cell acute lymphoblastic leukaemia. Br. J. Haematol. 160, 406–409 (2013).
Landau, D.A. et al. Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia. Cancer Cell 26, 813–825 (2014).
Oakes, C.C. et al. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat. Genet. 48, 253–264 (2016).
Heller, G. et al. Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia. Leukemia 30, 1861–1868 (2016).
Feinberg, A.P., Koldobskiy, M.A. & Göndör, A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 17, 284–299 (2016).
Greenblatt, S.M. & Nimer, S.D. Chromatin modifiers and the promise of epigenetic therapy in acute leukemia. Leukemia 28, 1396–1406 (2014).
Roberts, K.G. & Mullighan, C.G. Genomics in acute lymphoblastic leukaemia: insights and treatment implications. Nat. Rev. Clin. Oncol. 12, 344–357 (2015).
Woods, B.A. & Levine, R.L. The role of mutations in epigenetic regulators in myeloid malignancies. Immunol. Rev. 263, 22–35 (2015).
Shen, H. & Laird, P.W. Interplay between the cancer genome and epigenome. Cell 153, 38–55 (2013).
Oakes, C.C. et al. Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. Cancer Discov. 4, 348–361 (2014).
Amabile, G. et al. Dissecting the role of aberrant DNA methylation in human leukaemia. Nat. Commun. 6, 7091 (2015).
Shih, A.H. et al. Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer Cell 27, 502–515 (2015).
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).
Pasqualucci, L. et al. Expression of the AID protein in normal and neoplastic B cells. Blood 104, 3318–3325 (2004).
Gorre, M.E. & Sawyers, C.L. Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr. Opin. Hematol. 9, 303–307 (2002).
Roche-Lestienne, C. et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100, 1014–1018 (2002).
Branford, S., Melo, J.V. & Hughes, T.P. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood 114, 5426–5435 (2009).
Cortes, J. et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood 110, 4005–4011 (2007).
Woyach, J.A. et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N. Engl. J. Med. 370, 2286–2294 (2014).
Liu, T.M. et al. Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood 126, 61–68 (2015).
Burger, J.A. et al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat. Commun. 7, 11589 (2016).
Ahn, I.E. et al. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood 129, 1469–1479 (2017).
Smith, C.C. et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485, 260–263 (2012).
Goto, E. et al. Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment. Blood 118, 1600–1609 (2011).
Maus, M.V., Grupp, S.A., Porter, D.L. & June, C.H. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123, 2625–2635 (2014).
Davila, M.L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra25 (2014).
Lee, D.W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).
Maude, S.L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
Restifo, N.P., Smyth, M.J. & Snyder, A. Acquired resistance to immunotherapy and future challenges. Nat. Rev. Cancer 16, 121–126 (2016).
Chung, E.Y. et al. CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis. J. Clin. Invest. 122, 2257–2266 (2012).
Sotillo, E. et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5, 1282–1295 (2015).
Jacoby, E. et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat. Commun. 7, 12320 (2016).
Gardner, R. et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 127, 2406–2410 (2016).
Rayes, A., McMasters, R.L. & O'Brien, M.M. Lineage switch in MLL-rearranged infant leukemia following CD19-directed therapy. Pediatr. Blood Cancer 63, 1113–1115 (2016).
Armstrong, S.A. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat. Genet. 30, 41–47 (2002).
Evans, A.G. et al. Evolution to plasmablastic lymphoma evades CD19-directed chimeric antigen receptor T cells. Br. J. Haematol. 171, 205–209 (2015).
Mullighan, C.G. et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322, 1377–1380 (2008).
Bardini, M. et al. Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement. Leukemia 29, 38–50 (2015).
Oshima, K. et al. Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 113, 11306–11311 (2016).
Mullighan, C.G. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011).
Ma, X. et al. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia. Nat. Commun. 6, 6604 (2015).
Meyer, J.A. et al. Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat. Genet. 45, 290–294 (2013).
Tzoneva, G. et al. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat. Med. 19, 368–371 (2013).
Li, B. et al. Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL. Nat. Med. 21, 563–571 (2015).
Ariës, I.M. et al. Towards personalized therapy in pediatric acute lymphoblastic leukemia: RAS mutations and prednisolone resistance. Haematologica 100, e132–e136 (2015).
Jones, C.L. et al. MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia. Blood 126, 2202–2212 (2015).
Estey, E., Keating, M.J., Pierce, S. & Stass, S. Change in karyotype between diagnosis and first relapse in acute myelogenous leukemia. Leukemia 9, 972–976 (1995).
Raghavan, M. et al. Segmental uniparental disomy is a commonly acquired genetic event in relapsed acute myeloid leukemia. Blood 112, 814–821 (2008).
Parkin, B. et al. Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia. Blood 121, 369–377 (2013).
Sood, R. et al. Somatic mutational landscape of AML with inv(16) or t(8;21) identifies patterns of clonal evolution in relapse leukemia. Leukemia 30, 501–504 (2016).
Krönke, J. et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood 122, 100–108 (2013).
Nadeu, F. et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood 127, 2122–2130 (2016).
Pui, C.H. et al. Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol. 16, 465–474 (2015).
Kim, J.Y. & Gatenby, R.A. Quantitative clinical imaging methods for monitoring intratumoral evolution. Methods Mol. Biol. 1513, 61–81 (2017).
Batlevi, C.L., Matsuki, E., Brentjens, R.J. & Younes, A. Novel immunotherapies in lymphoid malignancies. Nat. Rev. Clin. Oncol. 13, 25–40 (2016).
Notta, F. et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science 351, aab2116 (2016).
Sun, J. et al. Clonal dynamics of native haematopoiesis. Nature 514, 322–327 (2014).
Busque, L. et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 88, 59–65 (1996).
Kwok, B. et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood 126, 2355–2361 (2015).
Young, A.L., Challen, G.A., Birmann, B.M. & Druley, T.E. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016).
Jones, P.A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).
We thank M. Mittelbrunn (CBM-Hospital 12 de Octubre, Madrid, Spain), X.S. Puente (Universidad de Oviedo, Oviedo, Spain), P. Menéndez (J. Carreras Leukemia Research Institute, Barcelona, Spain), R. Rabadán (Columbia University, New York, New York, USA), J. Soulier (Université Paris Diderot, Paris, France) and all members of our labs for their helpful comments on the manuscript. A.A.F. is supported by grants from the National Cancer Institute (NCI) of the National Institutes of Health (NIH), the Leukemia & Lymphoma Society, the Chemotherapy Foundation and the Rally Foundation. C.L.-O. is supported by grants from European Union (DeAge, ERC-Advanced Grant), Ministerio de Economía y Competitividad SAF2014-52413-R, Instituto de Salud Carlos III (RTICC), CIBERONC, Plan Feder, and EDP Foundation. The generous support by J.I. Cabrera is also acknowledged.
The authors declare no competing financial interests.
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Ferrando, A., López-Otín, C. Clonal evolution in leukemia. Nat Med 23, 1135–1145 (2017). https://doi.org/10.1038/nm.4410
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