Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome

Publication date: Available online 11 July 2019Source: Cancer CellAuthor(s): Maurice Labuhn, Kelly Perkins, Sören Matzk, Leila Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislavskiy, Thomas Risch, Raj Bhayadia, David Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Iotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey TaubSummaryMyeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research

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Publication date: 12 August 2019Source: Cancer Cell, Volume 36, Issue 2Author(s): Yehudit Birger, Ruth Shiloh, Shai IzraeliStudies of the mechanisms of acute leukemia transformation from a preleukemic state in humans are hampered by the absence of clinical preleukemia syndromes. In this issue of Cancer Cell, Labuhn et al. provide a functional genomics view on the leukemic evolution from congenital preleukemia in children with Down syndrome.
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research
(University of Oxford) Researchers at the University of Oxford, in collaboration with colleagues from Hannover Medical School and Martin-Luther-University Halle-Wittenberg, have discovered the specific gene mutations that are required for the development of leukaemia in children with Down's syndrome.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
(University of Oxford) Researchers at the University of Oxford, in collaboration with colleagues from Hannover Medical School and Martin-Luther-University Halle-Wittenberg, have discovered the specific gene mutations that are required for the development of leukemia in children with Down syndrome.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
Publication date: Available online 29 March 2019Source: Mutation Research/Genetic Toxicology and Environmental MutagenesisAuthor(s): David Tweats, David A. Eastmond, Anthony M. Lynch, Azeddine Elhajouji, Roland Froetschl, Micheline Kirsch-Volders, Francesco Marchetti, Kenichi Masumura, Francesca Pacchierotti, Maik SchulerAbstractAneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemica...
Source: Mutation Research Genetic Toxicology and Environmental Mutagenesis - Category: Genetics & Stem Cells Source Type: research
Adauto Lima Cardoso1, Bruno Evaristo de Almeida Fantinatti1, Natália Bortholazzi Venturelli1, Bianca de Oliveira Carmello1, Rogério Antonio de Oliveira2 and Cesar Martins1* 1Integrative Genomics Laboratory, Department of Morphology, Institute of Biosciences, São Paulo State University – Universidade Estadual Paulista, Botucatu, Brazil 2Department of Biostatistics, Institute of Biosciences, São Paulo State University – Universidade Estadual Paulista, Botucatu, Brazil Supernumerary B chromosomes are dispensable elements found in several groups of eukaryotes, and their impact...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
In conclusion, we have shown the safety and efficacy of Vemurafenib in a pediatric patient with DS affected by PXA. Ethics Statement This study was carried out in accordance with the recommendations of the Internal Review Board of the Bambino Gesù Children's Hospital with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Internal Review Board of the Bambino Gesù Children's Hospital. Informed Consent The authors declare that written informed consent was obtained from the pat...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
B-acute lymphoblastic leukemia (B-ALL) in patients with Down syndrome (DS) has a worse prognosis than non-DS B-ALL. However, associated cytogenetic alterations may alter the prognosis. Here we discuss a 13-year-old female with DS presenting with leg pain, fevers, white blood cell count 12.8 k/ul, hemoglobin 7.7 g/dL, platelets 31 k/ul, and 60.9% blasts on differential. Flow cytometry identified B-lymphoblasts (positive for CD19, cytoCD79a, cytoCD22, CD34, CD10, TdT, and CD45 (dim)) and bone marrow biopsy demonstrated sheets of B-lymphoblasts.
Source: Cancer Genetics and Cytogenetics - Category: Genetics & Stem Cells Authors: Source Type: research
Publication date: Available online 29 March 2019Source: Mutation Research/Genetic Toxicology and Environmental MutagenesisAuthor(s): David Tweats, David Eastmond, Anthony M. Lynch, Azeddine Elhajouji, Roland Froetschl, Micheline Kirsch-Volders, Francesco Marchetti, Kenichi Masumura, Francesca Pacchierotti, Maik SchulerAbstractAneuploidy is regarded as a hallmark of cancer, however, its role is complex with both pro- and anti-carcinogenic effects evident. In this IWGT review, we consider the role of aneuploidy in cancer biology; cancer risk associated with constitutive aneuploidy; rodent carcinogenesis with known chemical a...
Source: Mutation Research Genetic Toxicology and Environmental Mutagenesis - Category: Genetics & Stem Cells Source Type: research
Publication date: Available online 20 December 2018Source: Clinical Lymphoma Myeloma and LeukemiaAuthor(s): Noura Maarouf, Sonia Mahmoud, Reham Khedr, Leslie Lehmann, Khaled Shaaban, Sherine Ibrahim, Sonya Fahmy, Omneya Hassanain, Nouran Nader, Alaa ElhaddadAbstractIntroductionAcute megakaryoblastic leukemia is a rare subtype of pediatric AML with poor outcomes in non-Down syndrome patients. Published outcomes are poor and prognostic factors have not been clearly determined.MethodsTo evaluate the prognostic significance of various cytogenetic abnormalities and minimal residual disease (MRD) status by flow cytometry after i...
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
Acute megakaryoblastic leukemia is a rare subtype of pediatric AML with poor outcomes in non-Down syndrome patients. Published outcomes are poor and prognostic factors have not been clearly determined.
Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Source Type: research
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