Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib

Blood ◽  
2003 ◽  
Vol 102 (12) ◽  
pp. 4187-4190 ◽  
Author(s):  
Kathryn Wilkinson ◽  
Elvira R. P. Velloso ◽  
Luiz Fernando Lopes ◽  
Charles Lee ◽  
Jon C. Aster ◽  
...  
Keyword(s):  
Coiled Coil ◽  
Growth Factor Receptor ◽  
Myeloproliferative Disorders ◽  
Cytogenetic Response ◽  
Chromosome Band ◽  
Therapeutic Implications ◽  
Rational Drug ◽  
Receptor Beta

Abstract Eosinophilia is common in myeloproliferative disorders (MPDs) with abnormalities of chromosome band 5q31-33, including those that present with t(1;5)(q23;q33). With the development of rational drug therapy, characterization of the molecular targets for these translocations could guide treatment and affect patient survival. We cloned the t(1;5)(q23;q33) and showed that it fuses platelet-derived growth factor receptor beta (PDGFRB) to the coiled-coil domains of a novel partner protein, myomegalin. Using two-color interphase fluorescence in situ hybridization (FISH), we also demonstrated that the eosinophils are clonal in these disorders. Imatinib mesylate has recently been shown to be efficacious in MPDs with PDGFR activation. Therefore, following our molecular studies, we were able to redirect this patient's treatment. Although she had refractory and progressive disease, once imatinib was started, complete clinical and hematologic remission, as well as major cytogenetic response, was achieved. Given the therapeutic implications, our findings stress the need to aggressively investigate the molecular basis of these diseases, with emphasis on the PDGFR family. (Blood. 2003;102: 4187-4190)

The Platelet-Derived Growth Factor Receptor beta Fuses to Two Distinct Loci at 3p21 in Imatinib Responsive Chronic Eosinophilic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3253-3253 ◽  
Author(s):  
Claire Curtis ◽  
Jane F. Apperley ◽  
Raymond Dang ◽  
Michael Jeng ◽  
Jason Gotlib ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tyrosine Kinase ◽  
Blast Crisis ◽  
Coiled Coil ◽  
Growth Factor Receptor ◽  
Myeloproliferative Disorders ◽  
Rt Pcr ◽  
Chronic Eosinophilic Leukemia ◽  
Amino Terminal ◽  
Exon 11

Abstract We have identified three patients (2 adults, one infant) who presented with BCR-ABL negative eosinophilic myeloproliferative disorders. Cytogenetic analysis revealed a t(1;3;5)(p36;p21;q33) for case 1 and a t(3;5)(p21–25;q31–35) for cases 2 and 3. Two-color fluorescence in situ hybridization (FISH) using differentially labelled probes flanking PDGFRB indicated that this gene was disrupted in all three cases. 5′ rapid amplification of cDNA ends (5′RACE) for case 1 identified an in-frame mRNA fusion of exon 9 of the WDR48 gene at 3p21 to exon 12 of PDGFRB. The chimeric mRNA is predicted to encode a 872 amino acid fusion protein that retains the amino terminal WD repeat region of WDR48 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRbeta. Cases 2 and 3 were negative for the WDR48-PDGFRB fusion mRNA by RT-PCR using several combinations of primers. 5′RACE PCR from case 2 RNA identified a fusion involving a second 3p21 gene: GOLGA4 exon 11 was fused in-frame to exon 11 of PDGFRB. Exactly the same fusion was found in case 3. The predicted 991 amino acid protein included the amino terminal coiled-coil domain of GOLGA4 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRbeta. Interestingly, both WDR48 and GOLGA4 are involved in endocytic shuttling pathways. The presence of all fusions was confirmed by RT-PCR and identification of the genomic breakpoints. Imatinib, a known inhibitor of PDGFRbeta, selectively blocked the growth of patient CFU-GM for case 2. Following the identification of PDGFRB rearrangements, all three patients were treated with imatinib. Case 1 was in transformation, but responded rapidly to minimal doses of imatinib (800mg daily for 4 days) with complete cytogenetic remission but remained pancytopenic. Blast crisis recurred 8 months later, responded similarly to 3 days of imatinib, but the patient died 2 months later of invasive fungal infection. Case 2 responded clinically and remains in sustained cytogenetic and molecular remission (nested RT-PCR negative for GOLGA4-PDGFRB). Case 3 (a 13 month old boy) had a complete hematologic response to 50mg/day imatinib but the t(3;5) was still seen in 40% of metaphases at 3 months. We conclude that PDGFRB fuses to diverse partner genes to give rise to atypical MPDs. Although very rare, identification of these fusions is critical for proper management of affected individuals.

Assignment by in situ hybridization of a fibroblast growth factor receptor gene to human chromosome band 10q26

1991 ◽  
Vol 87 (1) ◽  
pp. 84-86 ◽  
Author(s):  
Marie-Genevi�ve Mattei ◽  
Agn�s Moreau ◽  
Marie-Claude Gesnel ◽  
Elisabeth Houssaint ◽  
Richard Breathnach
Keyword(s):  
In Situ Hybridization ◽  
Growth Factor ◽  
Human Chromosome ◽  
Fibroblast Growth Factor Receptor ◽  
Receptor Gene ◽  
Growth Factor Receptor ◽  
Chromosome Band ◽  
Fibroblast Growth ◽  
Human Chromosome Band

The Use of Advanced Analytical Techniques for Characterization of the Chemical, Physical, and Crystallographic Nature of a Surface

1973 ◽  
Vol 31 ◽  
pp. 132-133 ◽  
Author(s):  
R. E. Herfert
Keyword(s):  
Surface Characterization ◽  
Analytical Techniques ◽  
X Ray Diffraction ◽  
Depth Of Penetration ◽  
X Ray ◽  
The Past ◽  
Transmission Electron ◽  
Scanning Electron

Studies of the nature of a surface, either metallic or nonmetallic, in the past, have been limited to the instrumentation available for these measurements. In the past, optical microscopy, replica transmission electron microscopy, electron or X-ray diffraction and optical or X-ray spectroscopy have provided the means of surface characterization. Actually, some of these techniques are not purely surface; the depth of penetration may be a few thousands of an inch. Within the last five years, instrumentation has been made available which now makes it practical for use to study the outer few 100A of layers and characterize it completely from a chemical, physical, and crystallographic standpoint. The scanning electron microscope (SEM) provides a means of viewing the surface of a material in situ to magnifications as high as 250,000X.

A very rapid in situ Kikuchi technique to determine relative crystal misorientation

1988 ◽  
Vol 46 ◽  
pp. 830-831
Author(s):  
J. I. Bennetch
Keyword(s):  
Electron Beam ◽  
Analytical Techniques ◽  
Superplastic Forming ◽  
The Other ◽  
Kikuchi Pattern ◽  
Kikuchi Line ◽  
Line Analysis

In a recent study of the superplastic forming (SPF) behavior of certain Al-Li-X alloys, the relative misorientation between adjacent (sub)grains proved to be an important parameter. It is well established that the most accurate way to determine misorientation across boundaries is by Kikuchi line analysis. However, the SPF study required the characterization of a large number of (sub)grains in each sample to be statistically meaningful, a very time-consuming task even for comparatively rapid Kikuchi analytical techniques.In order to circumvent this problem, an alternate, even more rapid in-situ Kikuchi technique was devised, eliminating the need for the developing of negatives and any subsequent measurements on photographic plates. All that is required is a double tilt low backlash goniometer capable of tilting ± 45° in one axis and ± 30° in the other axis. The procedure is as follows. While viewing the microscope screen, one merely tilts the specimen until a standard recognizable reference Kikuchi pattern is centered, making sure, at the same time, that the focused electron beam remains on the (sub)grain in question.

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