The allele burden of JAK2 mutations remains stable over several years in patients with myeloproliferative disorders
Alexandre TheocharidesJakob PasswegMichael MedingerR. LooserShifang LiHui Hao-ShenAndreas BuserAloïs GratwohlAndré TichelliRadek C. Skoda
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In a retrospective single center study we determined the time course of the JAK2-V617F or JAK2 exon 12 allele burden in DNA from purified granulocytes from 48 patients with myeloproliferative disorders. The percentage of change between the first and last sample in JAK2-V617F positive patients without cytoreductive therapy (n=16) was only +9% during a follow-up of 36±13 months, reflecting a remarkably stable mutant allele burden. When treatment with hydroxyurea was initiated during the course of the study, we observed a significant decrease of the JAK2-V617F allele burden (n=6). However, in JAK2-V617F positive patients who were already on hydroxyurea treatment before the first blood sampling (n=14), we observed stable allelic ratios with a variance of only +3% during a follow-up of 34±16 months. Our data suggest that in untreated myeloproliferative disorders patients, from whom samples at diagnosis are not available, the JAK2 allele burden determined at later stages could be equally informative.Keywords:
Myeloproliferative Disorders
JAK2 V617F
Abstract We have examined the effects of mutations in the six allele-specific modifier genes su(Hw), e(we), su(f), su(s), su(wa), and su(pr) on the expression of 18 modifiable alleles, situated at 11 loci. Ten of the modifiable alleles are associated with insertions of the gypsy retrotransposon and the others include alleles associated with insertions of copia and 412. We tested or retested 90 of the 108 possible combinations and examined the expression of modifiable alleles in flies mutant for pairs of modifier genes in various heterozygous and homozygous configurations. Our principal findings are: (1) a screen of 40,000 mutagenized X chromosomes yielded three new mutations in known modifier genes, but revealed no new modifier genes; (2) the modification effects of different mutations in a given modifier gene were qualitatively similar; (3) each of the six modifiers suppressed some modifiable alleles, enhanced others, and had no noticeable effect on still others; (4) the modifier genes could be placed in four classes, according to their effects on the gypsy-insertion alleles; and (5) the effects of mutations in different modifier genes combined additively. Implications of these results for models of modifier gene action are discussed.
Retrotransposon
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ABSTRACT We report here the results of a genetic analysis of the gene Delta (Dl) of Drosophila melanogaster. Dl has been mapped to the band 92A2, on the basis of two pieces of evidence: (1) this band is the common breakpoint of several chromosomal aberrations associated with Dl mutations and (2) recombination mapping of alleles of five different lethal complementation groups that are uncovered by Df(3R)DlFX3 (breakpoints at 91F11; 92A3). Dl was found to map most distally of all five complementation groups. The analysis of a large number of Dl alleles demonstrates the considerable genetic and functional complexity of Dl. Three types of Dl alleles are distinguishable. Most alleles behave as amorphic or hypomorphic recessive embryonic lethal alleles, which in addition cause various defects in heterozygosity over the wild-type allele. The defects are due to haplo-insufficient expression of the locus and can be suppressed by a duplication of the wild-type allele. The second class is comprised of three alleles with antimorphic expression. The phenotype of these alleles can only be reduced, rather than suppressed, by a duplication of the wild-type allele. The third group is comprised of three visible, predominantly hypomorphic alleles with an antimorphic component of phenotypic expression. The pattern of interallelic complementation is complex. On the one hand, there is a group of hypomorphic, fully penetrant embryonic lethal alleles which complement each other. On the other hand, most alleles, including all amorphic alleles, are viable over the visible ones; alleles of antimorphic expression, however, are lethal over visible alleles. These results are compatible with a rather complex genetic organization of the Dl locus.
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JAK2 V617F
Myeloproliferative Disorders
Hematology
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Chronic neutrophilic leukemia (CNL) is a rare disease and can cause considerable diagnostic difficulty. Although the V617F JAK2 mutation has been described by several groups to be associated with classical myeloproliferative disorders (MPD), this same mutation has been detected with a low incidence in atypical MPD, such as CNL. Here we report the presence of the V617F mutation in a CNL patient, who is unusual for having survived for more than 96 months, with little disease progression. It remains to be established what role this mutation, which gives cells a proliferative advantage, might play in the pathogenesis and prognosis of rare atypical MPD.
Myeloproliferative Disorders
Pathogenesis
JAK2 V617F
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ABSTRACT The mutations of the Abruptex locus in Drosophila melanogaster fall into three categories. There are recessive lethal alleles and viable alleles. The latter can be divided into suppressors and nonsuppressors of Notch mutations. The recessive lethals are lethal in heterozygous combination with Notch. As a rule the recessive lethals are lethal also in heterozygous combination with the viable alleles. Heterozygous combinations of certain viable alleles are also lethal. In such heterozygotes, one heteroallele is a suppressor of Notch and the other is a nonsuppressor. Other heterozygous combinations of viable alleles are viable and have an Abruptex phenotype. The insertion of the wild allele of the Abruptex locus as an extra dose (carried by a duplication) into the chromosomal complement of the fly fully restores the viability of the otherwise lethal heterozygotes if two viable alleles are involved. The extra wild allele also restores the viability of heterozygotes in which a lethal and a suppressor allele are present. If, however, a lethal and a nonsuppressor are involved, the wild allele only partly restores the viability, and the effect of the wild allele is weakest if two lethal alleles are involved. It seems likely that of the viable alleles the suppressors of Notch are hypermorphic and the nonsuppressors are hypomorphic. The lethal alleles share properties of both types, and are possibly antimorphic mutations. It is suggested that the locus is responsible for a single function which, however, consists of two components. The hypermorphic mutations are defects of the one component and the hypomorphic mutations of the other. In heterozygotes their cumulative action leads to decreased viability. The lethal alleles are supposed to be defects of the function as a whole. The function controlled by the locus might be a regulative function.
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Imprinting is a form of epigenetic gene regulation in which alleles are differentially regulated according to the parent of origin. The Mez1 gene in maize is imprinted such that the maternal allele is expressed in the endosperm while the paternal allele is not expressed. Three novel Mez1 alleles containing Mutator transposon insertions within the promoter were identified. These mez1-mu alleles do not affect vegetative expression levels or result in morphological phenotypes. However, these alleles can disrupt imprinted expression of Mez1. Maternal inheritance of the mez-m1 or mez1-m4 alleles results in activation of the normally silenced paternal allele of Mez1. Paternal inheritance of the mez1-m2 or mez1-m4 alleles can also result in a loss of silencing of the paternal Mez1 allele. The paternal disruption of imprinting by transposon insertions may reflect a requirement for sequence elements involved in targeting silencing of the paternal allele. The maternal disruption of imprinting by transposon insertions within the Mez1 promoter suggests that maternally produced MEZ1 protein may be involved in silencing of the paternal Mez1 allele. The endosperms with impaired imprinting did not exhibit phenotypic consequences associated with bi-allelic Mez1 expression.
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ABSTRACT Null and low enzyme activity alleles recovered from two natural populations were analyzed for a number of genetic and biochemical properties. Analysis of 58 mutations at 14 loci showed that all but one allele were genetically viable and fertile, four alleles were associated with chromosome rearrangements, 28 alleles retained some enzyme activity, 13 alleles formed an active heterodimer with active alleles and five alleles showed partial interallelic complementation. Available evidence indicates that this sample includes mutations resulting from lesions in both coding and regulatory sequences. Certain mutations may be caused by transposable element insertions.
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Abstract We have characterized a novel dominant allele of the sex-determining gene her-1 of Caenorhabditis elegans. This allele, called n695, results in the incomplete transformation of XX animals into phenotypic males. Previously characterized recessive her-1 alleles transform XO animals into phenotypic hermaphrodites. We have identified five new recessive her-1 mutations as intragenic suppressors of n695. Three of these suppressors are weak, temperature-sensitive alleles. We show that the recessive her-1 mutations are loss-of-function alleles, and that the her-1(n695) mutation results in a gain-of-function at the her-1 locus. The existence of dominant and recessive alleles that cause opposite phenotypic transformations demonstrates that the her-1 gene acts to control sexual identity in C. elegans.
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