Article

Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukemia: 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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    • "There are 2 hematologic categories of MDS in children: (1) refractory cytopenia with less than 2% blasts in the peripheral blood (PB) and less than 5% blasts in the bone marrow (BM) (most common pattern) and (2) refractory anemia with excess blasts with 2%–19% blasts in PB and 5%–19% blasts in BM. Of note, refractory anemia with excess blasts in transformation with 20%– 29% blasts in PB and BM was considered a 3rd category in the past; however, according to the current World Health Organization Classification, these cases now fall under the category of acute myeloid leukemia with MDS-related changes [10,11,13]. Our patient was an example of the 2nd category, refractory anemia with excess blasts. "
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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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