Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options

Department of Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
British Journal of Haematology (Impact Factor: 4.96). 04/2008; 140(6):610-24. DOI: 10.1111/j.1365-2141.2007.06958.x
Source: PubMed

ABSTRACT Myelodysplastic syndromes (MDS) and the mixed myelodysplastic/myeloproliferative disorder juvenile myelomonocytic leukaemia (JMML) are rare haematopoietic stem cell diseases in children. While MDS-initiating events remain largely obscure, a growing body of clinical, genetic and laboratory evidence suggests that JMML is, at least in part, caused by aberrant signal transduction resulting from mutations of components of the RAS signalling pathway. To date, haematopoietic stem cell transplantation cures more than half of children diagnosed with MDS or JMML. Research on genetic conditions predisposing to MDS in young age, such as inherited syndromes with bone marrow failure, may present important insights into MDS pathogenesis.

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    • "Concerning with the pathogenesis, genetic disturbances of RAS signaling pathway has been disclosed recently [2] [3]. "
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a most powerful immunotherapy for hematological malignancies. However, the impact of immunological disturbances as a result of allo-HSCT is not understood well. We experienced an 11-year-old boy who presented with systemic lupus erythemathosus (SLE) 10 years after unrelated cord blood transplantation of male origin for juvenile myelomonocytic leukemia (JMML) with monosomy 7. Bone marrow examination showed complete remission without monosomy 7. Genetic analysis of peripheral blood revealed mixed chimera with recipient cells consisting of <5% of T cells, 50-60% of B cells, 60-75% of NK cells, 70-80% of macrophages, and 50-60% of granulocytes. Significance of persistent mixed chimera as a cause of SLE is discussed.
    12/2012; 2012:619126. DOI:10.1155/2012/619126
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    • "Myelodysplastic syndrome (MDS) is a rare haematological disorder in childhood, accounting for <5% of all paediatric haematopoietic neoplasias (Passmore et al, 2003; Niemeyer & Kratz, 2008) . In the French–American–British (FAB) Cooperative Group classification, refractory anaemia with excess blasts (RAEB) is defined by dysplastic morphology in two or more cell lineages with more than 5% blasts and RAEB in transformation (RAEB-T) is defined as RAEB with 20–29% blasts. "
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    ABSTRACT: We report the outcome of 16 children with refractory anaemia with excess of blasts (RAEB; n = 4) and RAEB in transformation (RAEB-T; n = 12) following induction therapy with etoposide, cytarabine and mitoxantrone (ECM) prior to haematopoietic stem cell transplantation (HSCT). The median observation period was 77 months (range 5-123). Complete remission rate was 81% following induction; no toxic deaths occurred. Eight-year event-free survival and overall survival was 50% and 56%, respectively. None of the three patients with a complex karyotype survived, suggesting karyotype is a crucial prognostic factor for survival. This study indicates the safety and high remission rate of ECM and high survival rates after HSCT for paediatric RAEB and RAEB-T.
    British Journal of Haematology 06/2012; 158(5):657-61. DOI:10.1111/j.1365-2141.2012.09210.x · 4.96 Impact Factor
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    • "Children affected by specific congenital syndromes are at a higher risk of developing JMML or a related transient myeloproliferative disorder in infancy, and the identification of genes associated with these syndromes have provided unique insights into the pathogenesis of this myeloid malignancy . Recent discoveries have advanced our ability to make a firm molecular diagnosis in 85–90% of children (Fig 1) (Niemeyer & Kratz, 2008; Loh et al, 2009). Table I. "
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    ABSTRACT: Myeloid neoplasms derive from the pathological clonal expansion of an abnormal stem cell and span a diverse spectrum of phenotypes including acute myeloid leukaemia (AML), myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). Expansion of myeloid blasts with suppression of normal haematopoiesis is the hallmark of AML, whereas MPN is associated with over-proliferation of one or more lineages that retain the capacity to differentiate, and MDS is characterized by cytopenias and aberrant differentiation. MPD and MDS can progress to AML, which is likely due to the acquisition of cooperative mutations. Juvenile myelomonocytic leukaemia (JMML) is an aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap MPN/MDS by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukaemia, a similar disease in adults. While the current standard of care for patients with JMML relies on allogeneic haematopoietic stem cell transplant (HSCT), relapse is the most frequent cause of treatment failure. This review outlines our understanding of the genetic underpinnings of JMML with a recent update on the discovery of novel CBL mutations, as well as a brief review on current therapeutic approaches.
    British Journal of Haematology 03/2011; 152(6):677-87. DOI:10.1111/j.1365-2141.2010.08525.x · 4.96 Impact Factor
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