The Management of Neoplastic Disorders of Haematopoeisis in Children with Down's Syndrome

Lange, Beverly J.

doi:10.1046/j.1365-2141.2000.02027.x

Cited by 212 publications

(191 citation statements)

References 129 publications

(199 reference statements)

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“…1,2 The relative risk of acute leukemia in the first 5 years has been estimated to be 56 times that of non-DS individuals, 1,2 with an equal frequency of acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). 3 Many reports have described the special features of leukemia in children with DS. 1,[3][4][5][6][7][8] AML in DS children is characterized by unique features, so that its classification as a separate disease entity, ''myeloid leukemia of Down syndrome,'' has been proposed.…”

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Acute lymphoblastic leukemia and Down syndrome

Aricò

Ziino²,

Valsecchi

et al. 2008

Cancer

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BACKGROUND.The presenting features and treatment outcome of 120 patients with Down syndrome (DS) and childhood acute lymphoblastic leukemia (ALL) were compared with 6237 non‐DS patients treated in the same years.METHODS.We reviewed the database of 6 consecutive Italian Association of Pediatric Hematology and Oncology (AIEOP)‐ALL trials conducted between 1982 and 2004. Features of DS patients were compared with those of non‐DS patients.RESULTS.The 120 DS patients (1.9%) were more often girls (P = .027), aged ≥10 years (P = .014), and high risk according to National Cancer Institute (NCI) criteria (P = .045). The distribution of white blood cell count did not differ (P = .32). DS patients belonged less frequently to the current high‐risk group (P = .017). In all but 1 case they demonstrated B‐cell precursor (BCP) immunophenotype (P≤.001). TEL/AML1 molecular fusion transcript was found in only 1 of 44 (2.2%) tested patients. Induction death occurred more often in DS patients (4.2%, P = .009), but not failure to achieve remission. Leukemia relapse occurred in 31.6% of DS patients (vs 23.5%; P = .003), usually in the marrow. Remission death was more frequent in DS patients (4.2%, P = .03). Ten‐year event‐free survival and survival were significantly worse compared with non‐DS patients (P < 0.001). DS patients diagnosed since 1995 had a better outcome (P = .06) than those diagnosed in previous years, but still had worse outcomes than non‐DS patients (P = .04). Event‐free survival of DS patients at NCI standard risk was lower than that of non‐DS patients (P = .006).CONCLUSIONS.Presenting features of childhood ALL in DS differ from those in non‐DS patients. They are almost invariably characterized by BCP phenotype, and are often TEL/AML1 negative. Treatment results, although not as good as for non‐DS patients, improved progressively, with modern therapy and support allowing 75% to survive. Cancer 2008. © 2008 American Cancer Society.

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“…3 Many reports have described the special features of leukemia in children with DS. 1,[3][4][5][6][7][8] AML in DS children is characterized by unique features, so that its classification as a separate disease entity, ''myeloid leukemia of Down syndrome,'' has been proposed. 9 The exact features of ALL in DS children have not yet been clarified.…”

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confidence: 99%

Acute lymphoblastic leukemia and Down syndrome

Aricò

Ziino²,

Valsecchi

et al. 2008

Cancer

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“…TMD blasts are morphologically indistinguishable from those observed in AMKL, contributing to the hypothesis that the second disease is derived from the first. 1,3 It is likely that AMKL results from the acquisition of additional genetic mutations following remission of TMD.We recently reported that mutations in the essential X-linked hematopoietic transcription factor gene GATA1 are tightly associated with AMKL in Down syndrome. 4 We detected mutations in GATA1 in 6 out of 6 DS-AMKL samples, but did not find mutations in GATA1 in leukemic cells of patients with DS who had other types of acute leukemia, or in other patients with AMKL who did not have DS.…”

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Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis

Mundschau

Gurbuxani

Gamis

et al. 2003

Blood

224

123

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As many as 10% of infants with Down syndrome (DS) present with transient myeloproliferative disorder (TMD) at or shortly after birth. TMD is characterized by an abundance of blasts within the peripheral blood and liver, and notably undergoes spontaneous remission in the majority of cases. TMD may be a precursor to acute megakaryoblastic leukemia (AMKL), with an estimated 30% of TMD patients developing AMKL within 3 years. We recently reported that mutations in the transcription factor GATA1 are associated with DS-AMKL. To determine whether the acquisition of GATA1 mutations is a late event restricted to acute leukemia, we analyzed GATA1 in DNA from TMD patients. Here we report that GATA1 is mutated in the TMD blasts from every infant examined. These results demonstrate that GATA1 is likely to play a critical role in the etiology of TMD, and mutagenesis of GATA1 represents a very early event in DS myeloid leukemogenesis. IntroductionChildren with Down syndrome (DS) have a 10-to 20-fold increased risk of developing leukemia, in particular acute megakaryoblastic leukemia (AMKL). 1 Children with DS are also predisposed to a related myeloid disorder, termed transient myeloproliferative disorder (TMD). 2 As many as 10% of infants with DS develop TMD, in which immature megakaryoblasts accumulate in the peripheral blood and liver. TMD spontaneously resolves in most cases, without therapeutic intervention. However, severe and sometimes fatal forms of TMD do occur, with hepatic fibrosis and liver dysfunction. On the basis of the liver infiltration and the spontaneous remission, it has been speculated that TMD may arise from fetal liver hematopoietic progenitors. 2 Of note, approximately 30% of infants with DS and TMD develop AMKL within 3 years. TMD blasts are morphologically indistinguishable from those observed in AMKL, contributing to the hypothesis that the second disease is derived from the first. 1,3 It is likely that AMKL results from the acquisition of additional genetic mutations following remission of TMD.We recently reported that mutations in the essential X-linked hematopoietic transcription factor gene GATA1 are tightly associated with AMKL in Down syndrome. 4 We detected mutations in GATA1 in 6 out of 6 DS-AMKL samples, but did not find mutations in GATA1 in leukemic cells of patients with DS who had other types of acute leukemia, or in other patients with AMKL who did not have DS. Furthermore, we did not detect GATA1 mutations in DNAs from more than 75 other patients with acute leukemia or from 21 healthy individuals. Finally, we established that these mutations are somatically acquired, as remission samples from patients did not harbor GATA1 mutations. On the basis of these observations, we hypothesized that disruption of normal GATA-1 function is an essential step in the initiation or progression of megakaryoblastic leukemia in DS.To determine whether GATA1 mutations represent a late event that contributes to the acute phase of DS myeloid leukemia, we assayed DNA samples from the peripheral blood of infa...

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“…Also, the emergence of routine use of heparin during the induction therapy along with intensive care has made it possible to bring the disease under control. [45][46][47][48][49][50] These unique characteristics of this disease have recently attracted intense research interest. As in other types of leukemia where continuous cell lines are powerful research tools, studies using APLderived cell lines have contributed a large body of relevant data in efforts to unravel the pathobiology and leukemogenesis of APL.…”

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confidence: 99%

Clinico Hematological Profile of Acute Promyelocytic Leukemia

P¹

2017

HTIJ

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Background: Acute promyelocytic leukemia (APL) is a unique subtype of acute leukemia's. It has distinct Cytogenetics, clinical features, and biologic characteristics. Acute promyelocytic leukemia (APL) is caused by an arrest of leukocyte differentiation at the promyelocytic stage. The discovery and elucidation of the molecular pathogenesis for APL has led to first and only targeted therapy for leukemia. It is classified as AML M3 by the French-American-British (FAB) system and acute promyelocytic leukemia (APL) with translocation between chromosomes 15 and 17, that is t(15;17) in the World Health Organization (WHO) classification system. A total of 55cases of APL were diagnosed in the 7year period. (JAN-2009 to DEC 2015 The majority patients presented with gum bleeding 86.4% with peripheral smear showing pancytopenia (54.5%). Prothrombin time was done on 24cases, out of which 14cases(58.3%) showed increased PT values. Immunophenotyping was done in 4cases showed positive for MPO, CD13, CD33, CD117 and negative for CD 34. Cytogenetics analysis was done in 35cases showed (15; 17) (q22; q12) PML RARα.

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The Management of Neoplastic Disorders of Haematopoeisis in Children with Down's Syndrome

Cited by 212 publications

References 129 publications

Acute lymphoblastic leukemia and Down syndrome

Acute lymphoblastic leukemia and Down syndrome

Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis

Clinico Hematological Profile of Acute Promyelocytic Leukemia

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