Treatment and prognostic impact of transient leukemia in neonates with Down syndrome

Klusmann, Jan‐Henning; Creutzig, Ursula; Zimmermann, Martin; Dworzak, Michael; Jorch, Norbert; Langebrake, Claudia; Pekrun, Arnulf; Macakova-Reinhardt, Katarina; Reinhardt, Dirk

doi:10.1182/blood-2007-10-118810

Cited by 237 publications

(418 citation statements)

References 36 publications

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“…Although the incidence of neoplasms in DS does not differ significantly from that in treatment could be required for the patient with these lifethreatening symptoms. A small proportion of these TAM patients will die from their disease, usually due to liver failure/fibrosis [10,11].…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

Evolution of myeloid leukemia in children with Down syndrome

Saida

2016

Int J Hematol

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“…TL is sometimes associated with liver fibrosis, which is life threatening and often fatal. 4,5 Transforming growth factor-b1 and PDGF were reported to be key mediators in fibrogenesis. 22 Recently, we and others reported that PDGF and transforming growth factor-b1 were abundantly expressed in TL blasts.…”

Section: Role Of Scf/kit Signaling In Tl Of Down Syndrome T Toki Et Almentioning

confidence: 99%

“…8 Recent reports showed that KIT is also expressed in almost all TL patients. 5,9 However, little is known about the expression level of KIT and the functional roles of SCF/KIT pathway in TL.…”

Section: Introductionmentioning

confidence: 99%

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The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia

et al. 2008

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Transient leukemia (TL) has been observed in approximately 10% of newborn infants with Down syndrome (DS). Although treatment with cytarabine is effective in high-risk TL cases, approximately 20% of severe patients still suffer early death. In this study, we demonstrate abundant KIT expression in all 13 patients with GATA1 mutations, although no significant difference in expression levels was observed between TL and acute myeloid leukemia. Stem cell factor (SCF) stimulated the proliferation of the TL cells from five patients and treatment with the tyrosine kinase inhibitor imatinib suppressed the proliferation effectively in vitro. To investigate the signal cascade, we established the first SCF-dependent, DS-related acute megakaryoblastic leukemia cell line, KPAM1. Withdrawal of SCF or treatment with imatinib induced apoptosis of KPAM1 cells. SCF activated the RAS/MAPK and PI3K/AKT pathways, followed by downregulation of the pro-apoptotic factor BIM and upregulation of the anti-apoptotic factor MCL1. Although we found novel missense mutations of KIT in 2 of 14 TL patients, neither mutation led to KIT activation and neither reduced the cytotoxic effects of imatinib. These results suggest the essential role of SCF/KIT signaling in the proliferation of DSrelated leukemia and the possibility of therapeutic benefits of imatinib for TL patients.

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“…TAM is defined as clonal myeloproliferation and characterized by circulating megakaryoblasts in the peripheral blood (Roy et al 2012). TAM, occurring in approximately 10% neonates with DS (Klusmann et al 2008;Ishigaki et al 2011), is usually selflimiting and undergoes spontaneous regression. However, approximately 20%-30% cases are life-threatening due to respiratory distress or liver failure.…”

Section: Introductionmentioning

confidence: 99%

Plasma TGF-<i>β</i>1 Levels Are Elevated in Down Syndrome Infants with Transient Abnormal Myelopoiesis

Maeda

Imamura

et al. 2016

Tohoku J. Exp. Med.

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Infants with Down syndrome (DS) are at risk of developing a transient myeloproliferative disorder during the neonatal period, known as transient abnormal myelopoiesis (TAM). It is characterized by clonal myeloproliferation and is typically self-limiting. However, TAM can be a life-threatening disorder, when complicated by liver fibrosis. Here, we evaluated cytokine profiles in two male DS infants having TAM with or without liver dysfunction. The first patient, Patient 1, had hyperleukocytosis with cholestatic liver dysfunction, coagulopathy, and increased counts of blasts and was treated with exchange transfusion (ExT) due to the serious general condition. In Patient 1, serum interleukin (IL)-8 and plasma transforming growth factor (TGF)-β1 levels were markedly elevated before ExT (1,518.2 pg/mL and 17,635 pg/mL, respectively). After ExT, serum IL-8 and plasma TGF-β1 levels decreased to 40.7 pg/mL and 6,847 pg/mL, respectively. However, Patient 1 died on day 56 due to cholestatic liver dysfunction; namely, this patient represents fatal TAM. The second patient, Patient 2, had hyperleukocytosis with increased counts of blasts without liver dysfunction and was treated with cytarabine. In Patient 2, plasma TGF-β1 levels, but not plasma IL-8, were elevated (9,068 pg/mL and 28 pg/mL, respectively). Patient 2 was discharged on day 47. In summary, plasma TGF-β 1 levels were elevated in the two DS infants with TAM, regardless of the presence or absence of hepatic fibrosis. Importantly, fatal TAM is assoicated with the elevated serum level of IL-8. We thus propose that IL-8 may be involved in the pathogenesis of liver fibrosis.

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Treatment and prognostic impact of transient leukemia in neonates with Down syndrome

Cited by 237 publications

References 36 publications

Evolution of myeloid leukemia in children with Down syndrome

Evolution of myeloid leukemia in children with Down syndrome

The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia

Plasma TGF-<i>β</i>1 Levels Are Elevated in Down Syndrome Infants with Transient Abnormal Myelopoiesis

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