Familial myelodysplasia and acute myeloid leukaemia - A review

Centre for Medical Oncology, Barts & the London School of Medicine & Dentistry, London, UK.
British Journal of Haematology (Impact Factor: 4.71). 02/2008; 140(2):123-32. DOI: 10.1111/j.1365-2141.2007.06909.x
Source: PubMed


Familial occurrence of myelodysplasia (MDS) and/or acute myeloid leukaemia (AML) is rare but can provide a useful resource for the investigation of predisposing mutations in these myeloid malignancies. To date, examination of families with MDS/AML has lead to the detection of two culprit genes, RUNX1 and CEBPA. Germline mutations in RUNX1 result in familial platelet disorder with propensity to myeloid malignancy and inherited mutations of CEBPA predispose to AML. Unfortunately, the genetic cause remains obscure in most other reported pedigrees. Further insight into the molecular mechanisms of familial MDS/AML will require awareness by clinicians of new patients with relevant family histories.

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    • "The diversity of clinical features present in patients with MDS can be partly explained by the type of chromosomal abnormalities acquired, and can be observed in approximately 30–50% of primary MDS and 80% of secondary. Deletions, monosomy and trisomy trigger clonal proliferation of hematopoietic progenitor cells in the bone marrow, and these events are observed in most patients with MDS [9]. Many specific abnormalities are closely linked to prognosis and genomic instability increases the propensity to develop AML [10]. "
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    ABSTRACT: The myelodysplastic syndromes (MDS) are a clinically and cytogenetically heterogeneous group of clonal diseases. Clonal chromosomal abnormalities are observed in 30-50% of patients with MDS. The deletions are among the most common alterations, and often involve the long arms of chromosomes 5, 7, 8, 13, and 20 and the short arms of chromosomes 12 and 17. The advent of new technologies for the detection of genetic abnormalities led to the description of a new set of recurrent mutations, leading to new insights into the pathophysiology of MDS. The recent recognition that genes involved in the regulation of histone function (EZH2, ASXL1, and UTX) and DNA methylation (DNMT3A, IDH1/IDH2, and TET2) are frequently mutated in MDS, has led to the proposal that there is an important link between genetic and epigenetic alterations in this disease. In fact, regulatory factors have also been considered as miR-143/miR-145, miR-146a, miR-125a and MiR-21. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems. In recent years research has brought new insights into these diseases, but few of the findings are sufficiently robust to be incorporated into the clinical routine at this time. Thus, the aim of this study was to review the role of genetic factors involved in the diagnosis and development of the different phenotypes of MDS. Copyright © 2015 Elsevier Inc. All rights reserved.
    Blood Cells Molecules and Diseases 06/2015; 55(1):76-81. DOI:10.1016/j.bcmd.2015.04.003 · 2.65 Impact Factor
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    • "We propose that accumulating levels of physiological DNA damage perturb RNA splicing and thus impair the differentiation of specific progenitor sub-populations , possibly via de-regulation of epigenetic and DNA repair factors. This is consistent with previous studies which have demonstrated that genetic alterations in DNA repair genes can result in BM failure syndromes and familial MDS by altering differentiation of hematopoietic cells (Geiselhart et al., 2012; Owen et al., 2008). Furthermore, it is tempting to speculate that defective DNA repair in these progenitors may also fuel secondary events that predispose to AML transformation. "
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    ABSTRACT: Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing, and myeloid progenitor differentiation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 05/2015; 27(5):644-657. DOI:10.1016/j.ccell.2015.04.007 · 23.52 Impact Factor
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    • "Patients with germline RUNX1 mutations present with thrombocytopenia and frequent progression toward MDS/AML (Owen et al., 2008). Similarly, germline CEBPA and GATA2 mutations have been associated with AML and early-onset MDS/AML (Owen et al., 2008; Hahn et al., 2011). Among patients with typical MDS, late presentation makes it difficult to distinguish hereditary factors from aging and cumulative environmental exposures (Pfeilstö cker et al., 2007; Sekeres, 2010). "
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    ABSTRACT: Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 04/2015; 27(5). DOI:10.1016/j.ccell.2015.03.017 · 23.52 Impact Factor
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