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The Tel-Pdgfrß Fusion Gene Produces a Chronic

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The Tel-Pdgfrß Fusion Gene Produces a Chronic Leukemia (1999) 13, 1790–1803 1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu The Tel-PDGFR␤ fusion gene produces a chronic myeloproliferative syndrome in transgenic mice KA Ritchie1,2 AAG Aprikyan1,3, DF Bowen-Pope2, CJ Norby-Slycord1,2, S Conyers1, E Sitnicka4,5 SH Bartelmez4,5 and DD Hickstein1,3 1Medical Research Service, VA Puget Sound Health Care System, Seattle, WA; 5Seattle Biomedical Research Institute Seattle, WA; Department of 4Pathobiology School of Public Health, and Departments of 2Pathology, and 3Medicine, School of Medicine, University of Washingon, Seattle, WA, USA Chronic myelomonocytic leukemia (CMML) is a pre-leukemic with myeloid metaplasia (MMM), and granulocytes in chronic syndrome that displays both myelodysplastic and myeloprolif- myeloid leukemia (CML). All the MPS are characterized by erative features. The t(5;12) chromosomal translocation, present in a subset of CMML patients with myeloproliferation splenomegaly, and may display subacute clinical problems fuses the amino terminal portion of the ets family member, Tel, associated with the hyperplastic lineage (eg hyperviscosity in with the transmembrane and tyrosine kinase domains of plate- PV, thrombosis in ET). Over time, these diseases may evolve let-derived growth factor receptor ␤ (PDGFR␤) gene. To investi- into marrow failure. All of the MPS are associated with an gate the role of this fusion protein in the pathogenesis of increased risk of developing leukemia, best exemplified by ␤ CMML, we expressed the Tel-PDGFR fusion cDNA in hemato- CML, which progresses from a chronic phase to an acute poietic cells of transgenic mice under the control of the human CD11a promoter. Transgenic founders and their offspring leukemia in almost all patients. express the transgene specifically in hematopoietic tissues and The progression of myelodysplastic syndromes to increas- develop a myeloproliferative syndrome characterized by: over- ingly severe dysplasias, cytopenias, and ultimately to acute production of mature neutrophils and megakaryocytes in the myeloid leukemia (AML) signifies these conditions as pre-leu- bone marrow; splenomegaly with effacement of splenic archi- kemic states, and supports the multi-hit hypothesis of malig- tecture by extramedullary hematopoiesis; an abnormal popu- nant transformation. Similarly, the increased risk of leukemia lation of leukocytes co-expressing lymphoid and myeloid mark- ers; and increased numbers of colonies in in vitro bone marrow associated with the chronic myeloproliferative syndromes sug- CFU assays. All mice expressing the transgene exhibited at gests that they, too, are pre-leukemic states. In both syn- least one of these features of dysregulated myelopoiesis, and dromes, the dysregulation of hematopoiesis predisposes to 20% progressed to a myeloid or lymphoid malignancy. This leukemia. Investigation of possible mechanisms of this dysreg- murine model of CMML parallels a myeloproliferative syndrome ulation might elucidate early events in leukemogenesis. ␤ in humans and implicates the Tel-PDGFR fusion protein in Chronic myelomonocytic leukemia (CMML) is an unusual its pathogenesis. Keywords: Tel-PDGFR␤; myeloproliferative syndrome; transgenic myelodysplastic syndrome with features of both myelodyspla- mice sia and myeloproliferation. It is characterized by increased numbers of monocytes and sometimes granulocytes in the peripheral blood, and monocyte precursors in the marrow. Introduction CMML may be difficult to distinguish both clinically and histo- pathologically from CML, however, the presence of the Phila- Myelodysplastic syndromes (MDS) represent heterogeneous delphia chromosome and the bcr/abl fusion cDNA are diag- clinicopathologic conditions generally characterized by inef- nostic of CML. CMML may be further subtyped into a fective hematopoiesis.1,2 Peripheral blood counts are low myelodysplastic form (eg abnormal morphologies in several despite a usually hypercellular marrow. Also, peripheral blood lineages), or a myeloproliferative form, similar to CML yet erythrocytes, granulocytes, and platelets, and their precursors negative for the Philadelphia chromosome. A subset of CMML in the marrow demonstrate abnormal morphologies shows a distinctive t(5,12) chromosomal translocation, and shows features of both MDS and chronic myeloproliferative (dysplasia) (see Bain for review and description of the French– 4 American–British (FAB) classification scheme57). Those MDS syndrome. with increased numbers of blasts in the marrow may progress Insight into CMML was obtained by the cloning and sequencing of the t(5;12) chromosomal breakpoint, associated to acute myeloid leukemia, and therefore represent pre-leu- 5,6 kemic states. with a subset of CMML. This translocation creates a fusion The chronic myeloproliferative syndromes (MPS) are hema- gene between Tel, a newly identified member of the ETS fam- tologic diseases characterized by hematopoietic hyperprolifer- ily of transcription factors, and the platelet-derived growth fac- ␤ 7 ation.3 The bone marrow is hypercellular, but hematopoiesis tor receptor beta gene (PDGFR ). The fusion gene contains is effective and maturation is progressive, producing increased the first 154 amino acids of Tel, including a putative helix- numbers of mature elements in the peripheral blood. Classi- loop-helix domain thought to mediate protein–protein interac- fication of a particular MPS is based on the lineage that is tions. The breakpoint occurs such that the fusion mRNA enco- predominant in the periphery, ie erythrocytes in polycythemia des a protein which lacks the extracellular ligand binding domain of PDGFR␤, but includes the transmembrane and vera (PV), platelets in essential thrombocythemia (ET), mega- ␤ karyocytes (in the spleen) with myelofibrosis in myelosclerosis intracellular domains of PDGFR , including the split tyrosine kinase domains that mediate intracellular signalling. Both the oligomerization domain of Tel and the tyrosine kinase activity of PDGFR␤ are operative in the transformation of Ba/F3 Correspondence: KA Ritchie, Pathology and Lab Medicine Service cells.8,9 Both Tel10–19 and PDGFR␤20,21 have been found in a 113, VA Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108, USA; Fax: 206-764-2001 number of different translocation fusion genes associated with A Aprikyan and K Ritchie contributed equally to this work hematopoietic malignancies. The participation of PDGFR␤ in Received 16 March 1999; accepted 20 May 1999 malignant transformation and normal signalling pathways is Tel-PDGFR␤ transgenic mice develop a myeloproliferative syndrome KA Ritchie et al 1791 well characterized.7,22–24 However, the respective roles of Tel was then ligated into the HincII site of the MCS. Orientation and PDGFR␤ in the pathogenesis of CMML has yet to be and possible mutations were ruled out by DNA sequencing elucidated. using the primer pairs (a–d) and (c–e), and an automated DNA We used the human CD11a promoter, which directs tissue- sequencer (Applied Biosystems, Model 373). To preserve the specific expression of a human CD4 reporter gene in the leu- reading frame and amino acid composition of the junction, kocytes of transgenic mice,25 to express the human Tel- the NotI site in the MCS was digested and filled in with PDGFR␤ fusion gene in transgenic mice. Parallel to the Klenow and dNTPs. Finally, the FspI–SspI fragment containing endogenous mouse CD11a gene, this promoter directs the transmembrane and tyrosine kinase domains of PDGFR␤ expression of the reporter gene early in hematopoiesis, and was isolated from full length PDGFR␤ cDNA26 and ligated also in both myeloid and lymphoid leukocyte lineages. By 4 into this NotI site. Orientation and maintenance of the reading months of age, mice expressing the Tel-PDGFR␤ fusion pro- frame across the junction were confirmed by DNA sequencing tein exhibit dysregulated hematopoiesis with features similar using primer pair (c–e). The hGH mini-gene was included in to a human myeloproliferative syndrome. Older mice demon- the construct because it is reported to increase mRNA strate a low frequency of hematopoietic malignancies. stability.27 The entire construct (7.4 kb) was excised by Pvul–NsiI digestion, isolated from an agarose gel, purified using a Materials and methods Qiagen column, quantitated by absorbance at 260 nm, and sent to DNX (Princeton, NJ, USA) for microinjection. Mice Gene construct and transgenic mice received from DNX were screened for the presence of the transgene as described,25 using a probe for the hGH portion The construct used to generate the Tel-PDGFR␤ transgenic of the construct. mice consists of a 1.7-kb fragment from the human CD11a proximal promoter, a 463 bp cDNA fragment encoding the first 154 amino acids of Tel, a 3.3-kb cDNA fragment contain- Detection of Tel-PDGFR␤ expression by Western ing the entire transmembrane and intracellular domains of blotting PDGFR␤ (amino acids 511–1106 and 1787 bp of 3Ј untrans- lated region),26 and a 1.9 kb fragment containing the human Approximately 100 ␮l of mouse peripheral blood were growth hormone (hGH) mini-gene (Figure 1). The human CD4 obtained by retro-orbital bleeding. Erythrocytes were lysed by 28 cDNA was released from the CD11a promoter-hCD4-hGH an NH4 Cl-Tris hypotonic lysis method and the peripheral construct25 by BamHI digestion, and the portion containing blood leukocytes were washed twice in cold PBS, resus- the human CD11a promoter, the human growth hormone pended in lysis buffer (50 mm
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