2016
DOI: 10.1038/ng.3742
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Dynamics of clonal evolution in myelodysplastic syndromes

Abstract: To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previ… Show more

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Cited by 365 publications
(409 citation statements)
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“…A recent large-scale genetic analysis demonstrated that GATA-2 mutations, which were critical for clonal evolution in MDS, had a relatively weaker impact on the progression of AML (Makishima et al 2017). Chromosomal translocations involving GATA-2 upstream enhancer region (−77 kb), such as inv(3)(q21q26) and t(3;3) (q21;q26), contribute to the onset of AML (Gröschel et al 2014;Yamazaki et al 2014).…”
Section: Human Diseases Caused By Gata-2 Dysregulationmentioning
confidence: 99%
“…A recent large-scale genetic analysis demonstrated that GATA-2 mutations, which were critical for clonal evolution in MDS, had a relatively weaker impact on the progression of AML (Makishima et al 2017). Chromosomal translocations involving GATA-2 upstream enhancer region (−77 kb), such as inv(3)(q21q26) and t(3;3) (q21;q26), contribute to the onset of AML (Gröschel et al 2014;Yamazaki et al 2014).…”
Section: Human Diseases Caused By Gata-2 Dysregulationmentioning
confidence: 99%
“…Recurrent SF3B1 mutations are therefore likely to play a distinct biological role in MDS-RS pathogenesis. 8 Other studies have identified recurrent SF3B1 mutations in otherwise healthy elderly individuals as evidence that SF3B1 mutations are also involved in premalignant clonal hematopoiesis. 9 In MDS-RS, mitochondrial ferritin accumulates in the mitochondria of the erythroblasts, resulting in accumulation of characteristic ring sideroblasts (RSs), ineffective erythropoiesis, and anemia.…”
Section: Introductionmentioning
confidence: 99%
“…For example, mutations in U2AF1 tend to significantly coexist with those in ASXL1, whereas mutations in SF3B1 frequently coexist with those in DNMT3A. [41][42][43] Further efforts to understand the mechanistic and biological contributions of these coexisting mutations on splicing and hematopoiesis may greatly facilitate our understanding of how mutations in RNA splicing promote MDS development.What is the role of RNA splicing factors in MDS development vs maintenance?Mutations in SF3B1, SRSF2, and U2AF1 are consistently expressed in the heterozygous state concomitant with expression of the wild-type allele.1-3 Although the nature of these alterations as heterozygous missense mutations was initially assumed to suggest that they confer a gain of function, it is also now clear that the wild-type allele is absolutely required for cell survival in the setting of expression of the mutant allele 11,23,44 (Figure 2). In contrast, several recent studies have identified that ablation of the mutant RNA splicing factor allele appears to have no effect on cancer maintenance.…”
mentioning
confidence: 99%
“…The lack of requirement for RNA splicing factor mutations in disease maintenance would suggest that these mutations are critically important in disease initiation, a possibility supported by the fact that mutations in RNA splicing factors appear to be some of the earliest genetic events in MDS development. [41][42][43] However, there are currently no studies evaluating this question in genetically defined cells that are not already in a transformed state. These same mutations are also frequently present in clonal hematopoiesis of indeterminate potential, 45,46 a condition highly associated with increased frequency of development of MDS and other myeloid neoplasms.…”
mentioning
confidence: 99%
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