Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome

Saida, Satoshi; Watanabe, Kenichiro; Sato‐Otsubo, Aiko; Terui, Kiminori; Yoshida, Kenichi; Okuno, Yusuke; Toki, Tsutomu; Wang, Runan; Shiraishi, Yuichi; Miyano, Satoru; Kato, Ikunoshin; Morishima, Tatsuya; Fujino, Hisanori; Umeda, Katsutsugu; Hiramatsu, Hidefumi; Adachi, Souichi; Ito, Etsuro; Ogawa, Seishi; Ito, Mamoru; Nakahata, Tatsutoshi; Heike, Toshio

doi:10.1182/blood-2012-12-474387

Cited by 21 publications

(24 citation statements)

References 43 publications

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“…[9][10][11] In several cases, the same patient-specific GATA1-mutation was present in TMD and ML-DS, 12 implying a clonal evolution with the acquisition of additional mutations. 13 These observations argue that elimination of the preleukemic TMD clone would prevent the development of ML-DS.…”

Section: Introductionmentioning

confidence: 99%

Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study

et al. 2018

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Key Points• Low-dose cytarabine treatment reduced mortality in symptomatic TMD patients compared with the historical control.• An MRD monitoringbased low-dose cytarabine treatment does not prevent progression from preleukemic TMD to ML-DS. [per protocol analysis]; historical control: 22 6 4%, P Gray 5 .55). Thus, low-dose cytarabine treatment helped to reduce TMD-related mortality when compared with the historical control but was insufficient to prevent progression to ML-DS.

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Section: Introductionmentioning

confidence: 99%

Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study

et al. 2018

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“…We hypothesize that TAM xenograft models would be an attractive method for investigating the evolutionary process of leukemia. In contrast to a previous study in which TAM cells showed a limited ability to expand in immunodeficient mice [56], we established a xenograft model of TAM using NOD/Shi-scid, IL-2Rγnull (NOG) mice, which mimicked the progression of TAM to DS-AMKL [57]. The presence of the same GATA1 mutation was confirmed in the primary TAM cells and the engrafted cells in the NOG mice.…”

Section: Tam Xenograft Modelmentioning

confidence: 95%

“…2). Recent studies reveal that genetic intratumoral heterogeneity was evident not only in the ML-DS, but also in the TAM phase [57,62], and that ML-DS originated from one of the multiple subclones present in the TAM phase of the disease. NGS methodology also showed the precise frequency of GATA1 mutation in DS [40] and may be used in the future to make diagnostic and treatment decisions in DS-related myeloid disorders.…”

Section: Discussionmentioning

confidence: 99%

“…This research was originally published in Ref. [57] [62] interactions between genomic regulatory elements [70], and for epigenetic regulators, such as EZH2, in regulating various epigenetic events [71]. Mutations are also observed in members of signaling pathways, such as the JAK family of kinases, MPL, SH2B3, and multiple RAS pathway genes [62,69].…”

Section: Additional Genomic Events Induce Ml-dsmentioning

confidence: 99%

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Evolution of myeloid leukemia in children with Down syndrome

Saida

2016

Int J Hematol

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the general population, the distribution of malignancies is different [3]. Patients with DS show a unique spectrum of malignancies, with a 10-to 20-fold higher risk of acute leukemia and a lower incidence of solid tumors [3,4]. Death from malignancies other than leukemia is strikingly less common in patients of all ages in DS, and death from leukemia is more likely in children younger than 10 years of age with DS than in those without [5]. The most frequent form of leukemia during childhood, both with and without DS, is acute lymphoblastic leukemia (ALL), and the incidence of ALL in children with DS is approximately 20-fold higher than in non-DS children [3]. However, the most marked increase in incidence in DS infants is with acute megakaryoblastic leukemia (AMKL), a myeloid malignancy of platelet precursors. The relative risk of developing AMKL is estimated to be 500 times higher in children with DS than in the general population [6]. Unlike AMKL in non-DS patients, most AMKL associated with DS (DS-AMKL) patients usually respond well to chemotherapy.In most cases, DS-AMKL is preceded by a temporary form of megakaryoblastic leukemia unique to newborns with DS and known as transient abnormal myelopoiesis (TAM) or transient leukemia. TAM, a clonal myeloproliferative syndrome, presents in the fetus or a few days after birth and in most cases resolves spontaneously within 3 months [7,8]. Typically, TAM is characterized by the presence of high numbers of circulating blast cells expressing CD33, CD38, CD117, CD34, CD7, CD56, CD36, CD71, and CD42b [9], which are indistinguishable from blasts observed in DS-AMKL. More often, the clinical presentation of TAM varies from asymptomatic alterations in the blood count to disseminated leukemic infiltration. Clinically severe TAM (liver failure, pleural/pericardial effusion, ascites, renal failure, and coagulopathy) affects 10-30 % of patients with clinically diagnosed TAM, and Abstract Children with Down syndrome (DS) have a markedly increased risk of leukemia. They are at particular risk of acute megakaryoblastic leukemia, known as myeloid leukemia associated with DS (ML-DS), the development of which is closely linked to a preceding temporary form of neonatal leukemia called transient abnormal myelopoiesis (TAM). Findings from recent clinical and laboratory studies suggest that constitutional trisomy 21 and GATA1 mutation(s) cause TAM, and that additional genetic alteration(s) including those in epigenetic regulators and signaling molecules are involved in the progression from TAM to ML-DS. Thus, this disease progression represents an important model of multi-step leukemogenesis. The present review focuses on the evolutionary process of TAM to ML-DS, and advances in the understanding of perturbed hematopoiesis in DS with respect to GATA1 mutation and recent findings, including cooperating genetic events, are discussed.

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“…The authors postulated that leukemia progression requires a "third-hit driver," putative driver mutations resulting in aberrant activation of WNT, JAK-STAT, or MAPK-PI3K pathways and consequent overexpression of MYC (Nikolaev et al 2013 ). The presence of multiple subclones with varying leukemia-initiating potential and selfrenewal capacity was also suggested in a xenograft model of TAM: during serial transplantation of TAM-derived cells, divergent subclones with another GATA1 mutation and various copy number alterations emerged (Saida et al 2013 ). Epigenetic changes can also contribute to leukemogenesis in DS.…”

Section: Gata1 Gene and Ds-acute Myeloid Leukemogenesismentioning

confidence: 97%

Etiology of Leukemia in Children with Down Syndrome

Xavier

Taub

2016

Etiology of Acute Leukemias in Children

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Down syndrome (DS) or trisomy 21 is the most common congenital genetic abnormality in the United States, and affected individuals have a unique predisposition to develop acute leukemias early in life. It is estimated that children with DS have a 40-and 150-fold increased risk of developing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), respectively. The increase in leukemia risk is likely caused by endogenous alterations of genetic factors, including imbalances in chromosome 21-localized genes and altered biochemical pathways in DS cells. The hallmark features of DS-AML include the early development of a precursor disorder known as transient abnormal myelopoiesis (TAM), which clinically resembles AML but is transient in nature, and the presence of GATA1 (Xp11.23) mutations, which are detectable in the majority of TAM and DS-AML cases. On the other hand, DS-ALL leukemogenesis is linked to alterations in the CRLF2 gene and associated mutations affecting pathways involving either the JAK2 or RAS genes. In this chapter we review current concepts of mechanisms leading to mutagenesis and leukemia in DS.

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Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome

Cited by 21 publications

References 43 publications

Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study

Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study

Evolution of myeloid leukemia in children with Down syndrome

Etiology of Leukemia in Children with Down Syndrome

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