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: 4.71). 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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    • "JMML is a clonal myeloproliferative/myelodysplastic disorder of childhood characterized by overproduction of immature myeloid cells that variably retain the capacity to differentiate. Upregulation of RAS/MAPK signalling owing to germline and somatic mutations in PTPN11, NRAS, KRAS, NF1 and CBL is a major event implicated in this malignancy (13,46,47). Our data document that upregulated RRAS function represents a novel event contributing to JMML pathogenesis and/or disease progression. "
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    ABSTRACT: RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.
    Human Molecular Genetics 04/2014; 23(16). DOI:10.1093/hmg/ddu148 · 6.39 Impact Factor
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    • "Since the ERK1/2 pathway has a central role in both proliferation and differentiation, many processes in human development and organ maintenance are disturbed by its dysfunction, resulting in various clinical symptoms, such as a distinctive cranio-facial appearance, cardiac defects, musculocutaneous abnormalities, and mental retardation [74, 75]. Germline missense mutations in the SHP2-encoding PTPN11 gene are seen in approximately 50% of NS cases; this observation contributed to the identification of PTPN11 as the most common target of somatic mutations in JMML [76, 77]. The most frequent JMML-associated mutation, E76 K, confers an enhanced catalytic activity on SHP2 and requires Gab2 for the transformation of primary murine myeloid progenitors [69]. "
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    ABSTRACT: The docking proteins of the Grb2-associated binder (Gab) family have emerged as crucial signaling compartments in metazoans. In mammals, the Gab proteins, consisting of Gab1, Gab2, and Gab3, are involved in the amplification and integration of signal transduction evoked by a variety of extracellular stimuli, including growth factors, cytokines, antigens, and other molecules. Gab proteins lack the enzymatic activity themselves; however, when phosphorylated on tyrosine residues, they provide binding sites for multiple Src homology-2 (SH2) domain-containing proteins, such as SH2-containing protein tyrosine phosphatase 2 (SHP2), phosphatidylinositol 3-kinase regulatory subunit p85, phospholipase Cγ, Crk, and GC-GAP. Through these interactions, the Gab proteins transduce signals from activated receptors into pathways with distinct biological functions, thereby contributing to signal diversification. They are known to play crucial roles in numerous physiological processes through their associations with SHP2 and p85. In addition, abnormal Gab protein signaling has been linked to human diseases including cancer, cardiovascular disease, and inflammatory disorders. In this paper, we provide an overview of the structure, effector functions, and regulation of the Gab docking proteins, with a special focus on their associations with cardiovascular disease, cancer, and inflammation.
    01/2013; 2013:141068. DOI:10.1155/2013/141068
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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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