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. "
[Show abstract][Hide abstract]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.
Full-text · Article · Apr 2014 · Human Molecular Genetics
"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. "
[Show abstract][Hide abstract]ABSTRACT: Abstract ABSTRACT: Myelodysplastic syndrome (MDS) and pulmonary tumor thrombotic microangiopathy (PTTM) are independently rare in the pediatric population. This report describes an 11-year-old male patient who initially presented with respiratory distress and cardiovascular collapse. A large left main pulmonary artery embolus and multiple, smaller pulmonary thromboemboli were widely dispersed throughout both lungs. Despite aggressive supportive care he expired within seven hours of admission. A complete postmortem examination was performed, leading to the diagnoses of primary MDS and microthrombi in the lungs including the characteristic fibroproliferative lesions seen in PTTM. Individually, both conditions are extremely uncommon, therefore the coincidence of these two conditions in a child is singularly unique in the setting of MDS.
myelodysplastic syndrome, refractory anemia with excess blasts-2, pulmonary tumor thrombotic microangiopathy, pulmonary hypertension, right heart failure, cor pulmonale.
Full-text · Article · Oct 2013 · Pediatric and Developmental Pathology
"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 . "
[Show abstract][Hide abstract]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.