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[Cancer Research 64, 7216-7219, October 15, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

p53-Binding Protein 1 Is Fused to the Platelet-Derived Growth Factor Receptor ß in a Patient with a t(5;15)(q33;q22) and an Imatinib-Responsive Eosinophilic Myeloproliferative Disorder

Francis H. Grand1, Sonja Burgstaller2, Thomas Kühr2, E. Joanna Baxter1, Gerald Webersinke3, Josef Thaler2, Andrew J. Chase1 and Nicholas C. P. Cross1

1 Wessex Regional Genetics Laboratory, Salisbury and Human Genetics Division, University of Southampton, Southampton, United Kingdom; 2 Department of Internal Medicine, General Hospital Wels, Wels, Austria; and 3 Department of Internal Medicine, Hospital of the Sisters of Mercy, Linz, Austria


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
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We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22). TP53BP1 encodes 53BP1, a p53-binding protein that plays a role in cellular responses to DNA damage. The 53BP1-PDGFRß fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRß. The presence of the fusion was confirmed by two-color fluorescence in situ hybridization, reverse transcription-PCR, and by characterizing the genomic breakpoints. The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR. Imatinib, a known inhibitor of PDGFRß, blocked the growth of patient colony-forming unit, granulocyte-macrophage in vitro and produced a clinically significant response before relapse and subsequent death with imatinib-resistant disease. We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
The molecular characterization of reciprocal chromosomal translocations in myeloproliferative disorders has led to the identification of diverse tyrosine kinase fusion genes. These fusions encode chimeric proteins composed of an NH2-terminal partner joined in frame to the entire catalytic domain and COOH-terminal region of the kinase (1) . Typically, the partner proteins contain dimerization or oligomerization motifs, such as helix-loop-helix, leucine zipper, or coiled-coil domains, that are essential for the observed constitutive tyrosine kinase activity of the fusions and downstream signaling through growth-stimulatory and antiapoptotic pathways (1) . Broadly, tyrosine kinase fusions are believed to deregulate hemopoiesis in a manner analogous to BCR-ABL in chronic myeloid leukemia (CML). From a clinical standpoint, identification of patients with PDGFRA, PDGFRB, or ABL fusions is particularly important, because these individuals are responsive to imatinib mesylate (2, 3, 4) . To date, eight fusion partners for PDGFRB have been reported: TEL/ETV6, CEV14, HIP1, H4, RABEP1, PDE4DIP, HCMOGT-1, and NIN (refs. 5, 6, 7, 8 and references therein). Molecular cytogenetic evidence suggests that several additional partner loci remain to be identified (9) . Here we describe the identification of one such locus, TP53BP1 at 15q22, and document the response of cells harboring the TP53BP1-PDGFRB fusion to imatinib in vitro and in vivo.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Patient Details.
A 79-year-old man was admitted to hospital in September 2001 with dyspnea, fatigue, and weight loss. He presented with a generalized erythematous rash, leukocytosis, and splenomegaly. The peripheral blood counts at this time were: white blood cells 138 x 109/L, hemoglobin 4.0 g/dL, and platelets 92 x 109/L. A diagnosis of CML was made after bone marrow aspiration and biopsy, which showed granulocytic hyperplasia with a marked eosinophilia (45% of granulocytic cells) and a reduction of the erythroid and megakaryocytic series. In addition, histologic assessment of various skin biopsies exhibited a leukemic infiltrate with a preponderance of eosinophils. Bone marrow cytogenetics and reverse transcription-PCR analysis were negative for the Philadelphia (Ph) chromosome and BCR-ABL rearrangement, respectively; however, a t(5;15)(q33;q22) was seen in 21 of 21 metaphase cells. The possibility of a constitutional translocation was eliminated by karyotyping a phytohemagglutinin-stimulated peripheral blood sample. After diagnosis, the patient was treated with various agents (hydroxyurea, interferon {alpha}, busulfan, and mercaptopurine). Although normalization of the leukocyte count and a decrease in the severity of skin infiltrations was achieved initially, the responses were transient.

Treatment with imatinib was initiated in June 2002 after identification of a PDGFRB rearrangement and demonstration of sensitivity to imatinib in vitro (see below). At this time the predominant clinical issue was a grade 4 transfusion-dependent thrombocytopenia (platelets ranged between 6 and 18 x 109/L) and grade 4 anemia. After a starting dose of 400 mg of imatinib daily, the white blood cell count declined from 27 x 109/L to normal range at day 9, and the spleen size decreased from 20 cm to 15 cm. On day 36 treatment was interrupted due to development of grade 4 neutropenia. Because this adverse event did not resolve within 2 weeks, the dose of imatinib was reduced to 300 mg/day. Cytopenia caused four interruptions in the imatinib administration. During the course of imatinib treatment the platelet counts gradually increased, and the platelet transfusion requirement reduced from alternate days to once weekly. However, after ~5 months, resistance to imatinib developed, which could not be overcome by dose escalation. Grade 4 transfusion-resistant thrombocytopenia developed, and the patient died of an intracerebral hemorrhage.

In vitro Imatinib Sensitivity Assay.
Imatinib sensitivity was tested on colony-forming unit, granulocyte-macrophage (CFU-GM) growth before imatinib therapy. Peripheral blood mononuclear cells were separated using lymphoprep (Axis-Shield, Oslo, Norway) and grown in methylcellulose supplemented with growth factors (Stem Cell Technologies Ltd., Vancouver, British Columbia, Canada) at a cell density of 2 x 105 cells/mL in 2.5-cm Petri dishes. Imatinib (Novartis, Basel, Switzerland) was added to final concentrations of 0, 1, and 5 µmol/L. Colony numbers were scored at days 7 and 14 from triplicate plates, and the numbers compared with those obtained from normal individuals and patients with BCR-ABL-positive CML.

Fluorescence In situ Hybridization Analysis.
Fluorescence in situ hybridization for PDGFRB was performed with flanking cosmid probes as described previously (9) . Other clones were identified using the University of California Santa Cruz genome browser4 and obtained from the Sanger Institute (Hinxton, United Kingdom). Bacterial artificial chromosome DNA was grown, extracted, and labeled by nick translation with alkali stable digoxigenin or biotin-16–2'-deoxy-uridine-5'-triphosphate (Roche, Mannheim, Germany) and hybridized as described previously (9) .

PCR Methods.
The partner gene was identified by 5' rapid amplification of cDNA ends using the GeneRacer kit (Invitrogen, Paisley, United Kingdom). Briefly, ~5 µg of total RNA extracted using the Qiagen RNeasy kit (Qiagen Ltd., Boundary Court, United Kingdom) was dephosphorylated, decapped, and ligated to the GeneRacer RNA oligo according to the manufacturer’s instructions. The ligated RNA was reverse transcribed using Superscript II reverse transcriptase (Invitrogen) and random primers (100 ng). The first step 5' rapid amplification of cDNA ends PCR was performed using the 5' GeneRacer primer from the kit in combination with a reverse primer from PDGFRB exon 15 (2R: 5'-TGCTGCAGGAAGGTGTGTTTGTTG-3'). The PCR cycles were designed to amplify fragments up to 5 kb, with an annealing temperature of 66°C using the High Fidelity PCR Master kit (Roche) according to the manufacturer’s instructions. First-step products were diluted 1:200 before being used as template for the second-step PCR. Second step PCR was performed with the 5'GeneRacer nested primer and a reverse primer derived from PDGFRB exon 15 (1R: 5'-AGGTAGTCCACCAGGTCTCCGTA-3') under the same conditions as the first-step PCR. Products were cloned with the TOPO TA cloning kit for sequencing (Invitrogen) and sequenced. The presence of TP53BP1-PDGFRB mRNA was confirmed on random hexamer reverse-transcribed cDNA (8) using primers to TP53BP1 (3F: 5'-GGGGAACTGTACTACAGCATTGA-3') plus primer PDGFRB-1R. The genomic breakpoint was amplified using a forward genomic primer from TP53BP1 intron 23 (1F: 5'-ACCCGAAAGATCACAGAAAGTCC-3') and a reverse primer from PDGFRB intron 11 (int1R: 5'-GAGAGCAGGCCATGAGCAAAC-3'.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Involvement of PDGFRB.
To our knowledge, the t(5;15)(q33;q22) has not been described before; however, the breakpoint on chromosome 5 in combination with the clinical phenotype suggested that PDGFRB might be involved. To test this possibility we performed two-color fluorescence in situ hybridization using flanking cosmid probes that immediately flank this locus (9) . These probes both hybridized to band q33 on the normal copy of chromosome 5 but hybridized differentially to the der(5) and der(15) , indicating that the translocation did indeed target PDGFRB (Fig. 1A)Citation .



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  		Fig. 1. Fluorescence in situ hybridization analysis. A, a t(5;15) metaphase hybridized to differentially labeled cosmid probes flanking PDGFRB demonstrating disruption of this gene; B, a t(5;15) metaphase hybridized with bacterial artificial chromosome RP11–114F23 (red), which contains TP53BP1 and spans the chromosome 15 breakpoint, in combination with the bacterial artificial chromosome clone RP11–100O5 (green; downstream of PDGFRB). A fusion signal is seen on the der(5) as expected, but no signal is seen on the der(15).

 
Response to Imatinib In vitro and In vivo.
To test if the presumptive PDGFRB fusion gene was responsive to imatinib, we analyzed CFU-GM production in the presence of 0 µmol/L, 1 µmol/L, or 5 µmol/L imatinib. Peripheral blood from a normal control individual showed a nonspecific reduction in colony numbers of ~50% with 1 µmol/L imatinib at both days 7 and 14. An additional 10% reduction was seen with 5 µmol/L imatinib (Fig. 2A)Citation , and similar results were seen with an additional 10 normal controls (data not shown). The reduction was much greater for CFU-GM grown from the CML patient, used as a positive control, with ~90% growth inhibition in the presence of 1 µmol/L and 5 µmol/L imatinib at both days 7 and 14 (Fig. 2B)Citation . Similarly, marked inhibition was seen for CFU-GM grown from the t(5;15) patient, with >95% reduction in colony numbers at day 7 and 80% to 90% reduction at day 14 (Fig. 2C)Citation . These data suggested that the t(5;15)-associated disease was indeed sensitive to imatinib, and consequently the patient was treated with this compound. As described above, the leukocyte count and eosinophilia responded to imatinib, but the patient subsequently relapsed with imatinib-resistant disease. Unfortunately, no clinical material was available to investigate the molecular basis for imatinib resistance.



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  		Fig. 2. CFU-GM growth of blood mononuclear cells from (A) normal control, (B) a CML patient, and (C) the t(5;15)(q33;q22)-positive patient; bars, ±SEM.

 
Identification of the TP53BP1-PDGFRB Fusion.
All of the PDGFRB fusions reported to date result in an mRNA junction with the partner gene sequence spliced to PDGFRB exons 11 or 12. Therefore, to identify the t(5;15) partner we performed 5'-rapid amplification of cDNA ends PCR. Sequencing of the products revealed several clones in which exon 23 of TP53BP1 (accession no. AF078776) was fused in frame to PDGFRB exon 11 (Fig. 3A)Citation . The presence of the TP53BP1-PDGFRB fusion was confirmed initially by reverse transcription-PCR. As shown in Fig. 3BCitation , the fusion was specifically amplified from t(5;15) cells by single-step PCR but was not detectable in normal controls. The reciprocal PDGFRB-TP53BP1 product was not detectable by single-step or nested PCR. Amplification and sequencing of the genomic breakpoint confirmed the fusion of intron 23 of TP53BP1 to intron 10 of PDGFRB (Fig. 3C)Citation . TP53BP1-PDGFRB is predicted to be translated into a 247 KDa 53BP1-PDGFRß fusion protein that retains the NH2-terminal region and kinetochore binding domain from 53BP1 fused to the transmembrane and entire cytoplasmic domain of PDGFRß.



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  		Fig. 3. A, the mRNA fusion of TP53BP1 exon 23 to PDGFRB exon 11; B, amplification of the TP53BP1-PDGFRB fusion by single step reverse transcription-PCR from the t(5;15) patient but not normal controls (N1-N3). B1 and B2 are blanks. C, sequences surrounding the genomic breakpoints in TP53BP1 (underlined) and PDGFRB. The exact position of the breakpoint is ambiguous due to a short stretch of homology (GGG) between the two genes.

 
Confirmation of the Presence of TP53BP1-PDGFRB.
To additionally confirm the presence of a TP53BP1-PDGFRB fusion, we performed additional fluorescence in situ hybridization analysis. Bacterial artificial chromosome RP11–114F23 contains the entire TP53BP1 gene, and bacterial artificial chromosome RP11–100O5 is downstream (centromeric) of PDGFRB.4 Cohybridization of these two clones to t(5;15) metaphases revealed the expected green and red signals on the normal chromosomes 5 and 15, respectively, plus a fusion signal corresponding to TP53BP1-PDGFRB on the der(5; Fig. 1BCitation ). The expected TP53BP1 signal was not seen on the der(15) , suggesting this sequence had been deleted. A deletion at the breakpoint explains why reciprocal PDGFRB-TP53BP1 fusion transcripts were not detected and may also account for the fact that the breakpoint was assigned cytogenetically to 15q22 but TP53BP1 maps to 15q15.

Structure and Function of 53BP1 and the 53BP1-PDGFRß.
53BP1 is a component of the cellular response to DNA damage that was initially identified as a protein that binds to wild-type but not mutant p53 (10) . Subsequently, it has been shown that the BRCA1 COOH-terminus domains of 53BP1 bind to the central DNA-binding domain of p53 and enhance p53-mediated transcriptional activation (11 , 12) . After irradiation, 53BP1 is hyperphosphorylated in an ATM-dependent manner and colocalizes with H2AX and other factors at double-stranded DNA breaks (13 , 14) in a manner dependent on the conserved 53BP1 Tudor and Myb domains (15) . TP53BP1(–/–) mice are cancer prone, indicating that this gene functions as a tumor suppressor and manifests defects in DNA damage response and cell cycle checkpoint control (16) .

The t(5;15) is predicted to generate a chimeric protein that is structurally similar to other tyrosine kinase fusions. Therefore, it is very likely that 53BP1-PDGFRß is a constitutively active transforming oncogene, a notion strongly supported by the fact that patient CFU-GM were inhibited by imatinib and the observed clinical response. It is conceivable, however, that the t(5;15) also interferes with the DNA damage response, either by haploinsufficiency of TP53BP1 or through a dominant-negative effect of the fusion protein, which retains the Tudor and Myb domains but not the BRCA1 COOH-terminal domain (Fig. 4)Citation .



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  		Fig. 4. Schematic representation of 53BP1, PDGFRß, and the 53BP1-PDGFRß fusion protein.

 
As described above, constitutive activation of fusion tyrosine kinases is mediated by an oligomerization domain in the partner protein. We did not identify any helix-loop-helix or leucine zipper motifs in 53BP1, but the coiled-coil prediction program Coils v2.1 (17) 5 indicated the presence of three potential coiled-coil domains: amino acids 133 to 150 (window = 14; probability >94%); amino acids 731 to 744 (window = 14; probability >92%) and amino acids 798 to 818 (window = 21; probability >97%). It is possible that one or more of these domains is responsible for oligomerization of 53BP1-PDGFRß.

Concluding Remarks.
In summary, we have identified 53BP1-PDGFRß fusion as a consequence of a t(5;15)(q33;q22) in a patient with an atypical, CML-like myeloproliferative disorder. TP53BP1 is the ninth PDGFRB fusion partner to be identified and further expands the repertoire of imatinib-responsive abnormalities in hematologic disorders.


   FOOTNOTES
 
Grant support: Leukemia Research Fund of the United Kingdom.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Prof. Nicholas Cross, Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, United Kingdom. Phone: 44-1722-429080; Fax: 44-1722-338095; E-mail: n.c.p.cross{at}soton.ac.uk

4 Internet address: http://genome.ucsc.edu/ Back

5 Internet address: http://www.ch.embnet.org/software/COILS_form.html. Back

Received 6/ 7/04. Revised 7/28/04. Accepted 8/22/04.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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  8. Vizmanos JL, Novo FJ, Roman JP, et al NIN, a gene encoding a CEP110-like centrosomal protein, is fused to PDGFRB in a patient with a t(5;14)(q33;q24) and an imatinib-responsive myeloproliferative disorder. Cancer Res 2004;64:2673-6.[Abstract/Free Full Text]
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