Myeloid leukemia in children 4 years or older with Down syndrome often lacks GATA1 mutation and cytogenetics and risk of relapse are more akin to sporadic AML

Hasle, Henrik; Abrahamsson, Jonas; Arola, Mikko; Karow, Axel; O'Marcaigh, Aengus; Reinhardt, Dirk; Webb, D; Wering, Elisabeth van; Zeller, Bernward; Zwaan, C. Michel; Vyas, Paresh

doi:10.1038/sj.leu.2405060

Cited by 68 publications

(56 citation statements)

References 14 publications

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“…18 For this reason we used the age cut-off in our inclusion criteria, to avoid 'contamination' with non-GATA1 mutated AML cases in DS children. In addition, AML in children with DS older than 4 years of age is exceedingly rare.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…18 In addition, ML-DS patients with a history of transient myeloproliferative disease have a significantly better outcome than children with ML-DS without documented transient myeloproliferative disease. 19 Until now, no other prognostic factors have been identified in ML-DS.…”

mentioning

confidence: 99%

“…14 Regarding age in ML-DS, it has been proposed that DS children who present over 4 years of age do in fact suffer from sporadic AML occurring in a child with DS, rather than from a 'true' ML-DS. 18 For this reason we used the age cut-off in our inclusion criteria, to avoid 'contamination' with non-GATA1 mutated AML cases in DS children. In addition, AML in children with DS older than 4 years of age is exceedingly rare.…”

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confidence: 99%

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Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o ndren who present over 4 years of age are in fact suffering from sporadic AML occurring in a child with DS, rather than from 'true' ML-DS. 18 In addition, ML-DS patients with a history of transient myeloproliferative disease have a significantly better outcome than children with ML-DS without documented transient myeloproliferative disease. 19 Until now, no other prognostic factors have been identified in ML-DS.The leukemic blasts from the majority of patients with ML-DS (72%) show additional cytogenetic changes apart from the constitutional trisomy 21. 20 A previous international-BFM study, performed by Forestier et al., showed that the most frequent gains involved chromosomes 8 (27%), 21 (23%), 11 (8.1%), and 19 (7.4%), whereas chromosomes X (3.2%; only females), 5 (1.5%), and 7 (2.2%) were commonly monosomic. The most frequent partial imbalances were duplication 1q (16%), deletion 7p (10%), and deletion 16q (7.4%). 20 However, the potential clinical impact of these cytogenetic abnormalities is not known and has not been well studied, mainly due to the small numbers of patients in individual series. 9,10,[20][21][22] In current treatment protocols of non-DS pediatric AML patients, stratification is based on cytogenetics and response to therapy. 23 In ML-DS, no prognostic cytogenetic groups have yet been identified, nor any other prognostic factors allowing a risk-stratified approach.We, therefore, conducted a large international study of clinical and outcome data including cytogenetic records from children with ML-DS collected from 13 collaborative study groups. Our aim was to identify differences in outcome related to cytogenetics and clinical characteristics in ML-DS. This was approached by analyzing differences in the cumulative incidence of relapse (CIR), reflecting leukemia resistance, and hence avoiding the influence of toxic (non-leukemic) events on survival estimates. This may result in risk-group stratification and risk-group directed therapy for these patients in the future. In addition, we compared the outcome of ML-DS patients in the different cytogenetic groups with that of non-DS AML patients from the same era treated on AML-BFM regimens as a reference cohort. Methods PatientsData on 451 patients with ML-DS were collected from 13 collaborative study groups participating in the International AML-BFM Study Group. For comparison, a reference cohort of non-DS AML patients (n=543) from the same treatment era, kindly provided by the AML-BFM Study Group, was used. This study was approved by the Institutional Review Boards in accordance with local legislation and guidelines.Patients were eligible if diagnosed between January 1, 1995 and January 1, 2005. Patients who were not treated with curative intent from diagnosis were excluded. The data collected at diagnosis comprised karyotype, sex, age, white blood cell (WBC) count, hemoglobin level, platelet count, immunophenotypic data and FAB morphology. In addition, we collected data on treatment, such a...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study

et al. 2013

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“…(Chou, et al 2008, Klusmann, et al 2008, Tunstall-Pedoe, et al 2008 In most cases (~80%) TL resolves spontaneously without development of ML-DS later in life, however, in 20% of children TL is followed by ML-DS between 1-4 years of age ( Figure 3). (Hasle, et al 2008) It is currently unknown whether ML-DS may also occur without preceding TL, although it is perhaps unlikely. Moreover, it is unknown which factors exactly drive clonal evolution to ML-DS in these 20% of children, although research is ongoing to unravel this.…”

Section: Children With Down Syndromementioning

confidence: 99%

Pediatric Acute Myeloid Leukemia

Zwaan¹,

Heuvel‐Eibrink²

2011

Acute Leukemia - The Scientist's Perspective and Challenge

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“…It has been noted that DS patients with positive GATA1 mutations should be screened for leukemia regularly [16]. Monitoring GATA1 mutations in DS patients with leukemia may help hematologists in classifying and designing the management of DS patients with leukemia.…”

Section: Introductionmentioning

confidence: 99%

GATA1 Gene Polymorphisms in Down Syndrome Patients

Ponkhoon,

Bayarmagnai,

Jav

et al. 2017

Cent. Asian j. Med. Sci.

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Objectives: Down syndrome (DS) patients have a 500 fold higher possibility of developing acute megakaryoblastic leukemia (AMKL), compared with the general population. GATA1 mutations, acquired in the early prenatal stages, contributes to leukemogenesis in AMKL and has been the explanation for the cause of early hematopoietic disorders. The aim of this study was to investigate the influence of GATA1 gene polymorphisms in patients with DS. Methods: Thirty-nine DS patients, aged ≤ 4 years, were recruited into the study. GATA1 gene polymorphisms were identified by unidirectional deep sequencing. Results: GATA1 gene polymorphisms were identified in four patients: proband-11 had GATA1 gene polymorphism, NP_002040.1:p.His71Arg (rs374300356); proband-17 had NP_002040.1:p. Tyr69Cys; proband-19 had NP_002040.1:p.Lys100Arg; and proband-20 had NP_002040.1:p. Tyr69Cys. Analyzing these GATA1 gene polymorphisms with 14 different software programs to evaluate its pathogenicity showed that NP_002040.1:p.His71Arg had damaging effects on GATA1 gene function. Conclusion: We identified four GATA1 gene polymorphisms in this cohort of 39 patients. The polymorphism identified in proband-11 (NP_002040.1:p.His71Arg) has possible damaging effects on gene regulation, and thus, we recommend routine clinical examination in this patient.

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Myeloid leukemia in children 4 years or older with Down syndrome often lacks GATA1 mutation and cytogenetics and risk of relapse are more akin to sporadic AML

Cited by 68 publications

References 14 publications

Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study

Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study

Pediatric Acute Myeloid Leukemia

GATA1 Gene Polymorphisms in Down Syndrome Patients

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