Abstract
Children with constitutional trisomy 21 or Down's syndrome (DS) are predisposed to develop myeloid leukemia (ML) at a young age. DS-ML is frequently preceded by transient leukemia (TL), a spontaneously resolving accumulation of blasts during the newborn period. Somatic mutations of GATA1 in the blasts of TL and DS-ML likely function as an initiating event. We hypothesized that the phenotypic difference between TL and DS-ML is due to a divergent functional repertoire of the leukemia-initiating cells. Using an NOD/SCID model, we found that cells initiating DS-ML engrafted, disseminated to distant bone marrow sites, and propagated the leukemic clone in secondary recipients. In contrast, TL cells lacked the ability to expand and to migrate, but were able to persist in the recipient bone marrow. We found some evidence of genomic progression with 1 of 9 DS-ML samples and none of 11 TL samples harboring a mutation of N-RAS. The findings of this pilot study provide evidence for the functional impact of second events underlying the transformation of TL into DS-ML and a needed experimental tool for the functional testing of these promoting events.
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Hasle H, Clemmensen IH, Mikkelsen M . Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 2000; 355: 165–169.
Gamis AS, Woods WG, Alonzo TA, Buxton A, Lange B, Barnard DR et al. Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the children's cancer group study 2891. J Clin Oncol 2003; 21: 3415–3422.
Hitzler JK, Zipursky A . Origins of leukaemia in children with Down syndrome. Nat Rev Cancer 2005; 5: 11–20.
Zipursky A . Transient leukaemia—a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 2003; 120: 930–938.
Klusmann JH, Creutzig U, Zimmermann M, Dworzak M, Jorch N, Langebrake C et al. Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 2008; 111: 2991–2998.
Hitzler JK, Cheung J, Li Y, Scherer SW, Zipursky A . GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 2003; 101: 4301–4304.
Mundschau G, Gurbuxani S, Gamis AS, Greene ME, Arceci RJ, Crispino JD . Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 2003; 101: 4298–4300.
Rainis L, Bercovich D, Strehl S, Teigler-Schlegel A, Stark B, Trka J et al. Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 2003; 102: 981–986.
Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 2002; 32: 148–152.
Xu G, Nagano M, Kanezaki R, Toki T, Hayashi Y, Taketani T et al. Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome. Blood 2003; 102: 2960–2968.
Malinge S, Izraeli S, Crispino JD . Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 2009; 113: 2619–2628.
Vyas P, Crispino JD . Molecular insights into Down syndrome-associated leukemia. Curr Opin Pediatr 2007; 19: 9–14.
Dick JE . Stem cell concepts renew cancer research. Blood 2008; 112: 4793–4807.
Hong D, Gupta R, Ancliff P, Atzberger A, Brown J, Soneji S et al. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 2008; 319: 336–339.
Tanaka T, Tsudo M, Karasuyama H, Kitamura F, Kono T, Hatakeyama M et al. A novel monoclonal antibody against murine IL-2 receptor beta-chain. Characterization of receptor expression in normal lymphoid cells and EL-4 cells. J Immunol 1991; 147: 2222–2228.
Mazurier F, Doedens M, Gan OI, Dick JE . Rapid myeloerythroid repopulation after intrafemoral transplantation of NOD-SCID mice reveals a new class of human stem cells. Nat Med 2003; 9: 959–963.
Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.
Kennedy JA, Barabe F, Poeppl AG, Wang JC, Dick JE . Comment on ‘tumor growth need not be driven by rare cancer stem cells’. Science 2007; 318: 1722; author reply 1722.
Hasle H, Niemeyer CM, Chessells JM, Baumann I, Bennett JM, Kerndrup G et al. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 2003; 17: 277–282.
Creutzig U, Ritter J, Vormoor J, Ludwig WD, Niemeyer C, Reinisch I et al. Myelodysplasia and acute myelogenous leukemia in Down's syndrome. A report of 40 children of the AML-BFM Study Group. Leukemia 1996; 10: 1677–1686.
Lange BJ, Kobrinsky N, Barnard DR, Arthur DC, Buckley JD, Howells WB et al. Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood 1998; 91: 608–615.
Haferlach T, Bacher U, Haferlach C, Kern W, Schnittger S . Insight into the molecular pathogenesis of myeloid malignancies. Curr Opin Hematol 2007; 14: 90–97.
Wilson A, Trumpp A . Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 2006; 6: 93–106.
Avigdor A, Goichberg P, Shivtiel S, Dar A, Peled A, Samira S et al. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow. Blood 2004; 103: 2981–2989.
Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE . Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006; 12: 1167–1174.
Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635–638.
Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR . Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998; 393: 595–599.
Crispino JD . GATA1 in normal and malignant hematopoiesis. Semin Cell Dev Biol 2005; 16: 137–147.
Taub JW, Mundschau G, Ge Y, Poulik JM, Qureshi F, Jensen T et al. Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome. Blood 2004; 104: 1588–1589.
Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, Bennett P et al. Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 2008; 112: 4507–4511.
Li Z, Godinho FJ, Klusmann JH, Garriga-Canut M, Yu C, Orkin SH . Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet 2005; 37: 613–619.
Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 2008; 372: 1484–1492.
Gupta PB, Chaffer CL, Weinberg RA . Cancer stem cells: mirage or reality? Nat Med 2009; 15: 1010–1012.
Shackleton M, Quintana E, Fearon ER, Morrison SJ . Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 2009; 138: 822–829.
Acknowledgements
We thank Dr Alvin Zipursky for the inspiring discussions, Dr Mohamed Abdelhaleem for assistance with imaging, and the families of children with leukemia for their participation. This work was supported by the National Cancer Institute of Canada (Canadian Cancer Research Society), The Ontario Institute for Cancer Research, and The Hospital for Sick Children Foundation.
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John E Dick declares research contracts with CSL and Arius.
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Chen, J., Li, Y., Doedens, M. et al. Functional differences between myeloid leukemia-initiating and transient leukemia cells in Down's syndrome. Leukemia 24, 1012–1017 (2010). https://doi.org/10.1038/leu.2010.30
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DOI: https://doi.org/10.1038/leu.2010.30
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