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The myelodysplastic/myeloproliferative diseases (MDS/MPDs) are a heterogeneous group of myeloid neoplasms that share characteristics with chronic myeloproliferative diseases and myelodysplastic syndromes. The broad spectrum of clinical manifestations makes MDS/MPDs extremely difficult to diagnose and treat, with a median survival time of 1-5 years. No single gene defect has been firmly associated with MDS/MPDs, and no animal models have been developed for these diseases. The association of deletions on chromosome 20q with myeloid malignancies suggests the presence of unidentified tumor suppressor genes in this region. Here we show that the recently identified death inducer-obliterator (Dido) gene gives rise to at least 3 polypeptides (Dido1, Dido2, and Dido3) through alternative splicing, and we map the human gene to the long arm of chromosome 20. We found that targeting of murine Dido caused a transplantable disease whose symptoms and signs suggested MDS/MPDs. Furthermore, 100% of human MDS/MPD patients analyzed showed Dido expression abnormalities, which we also found in other myeloid but not lymphoid neoplasms or in healthy donors. Our findings suggest that Dido might be one of the tumor suppressor genes at chromosome 20q and that the Dido-targeted mouse may be a suitable model for studying MDS/MPD diseases and testing new approaches to their diagnosis and treatment.
Nonstandard abbreviations used: aCML, atypical chronic myeloid leukemia; AML, acute myeloblascic leukemia; BAC, bacterial artificial chromosome; BFU-E, burst forming unit-erythrocyte; CFU-GM, CFU-granuIocyte-macrophage; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; CMPD, chronic myeloproliferative disease; CT, cycle threshold(s); Didol, death inducer-obliterator 1 (also known as DIO-1); hDido, human Dido; JMML, juvenile myelomonocytic leukemia; mDido2, murme Dido2; MDS, rnyelodysplastic syndrome; MDS/MPD, myelodysplastic/myeloproliferative disease; MEF, mouse embryonic fibroblasts; NLS, nuclear localization signal; RACE, rapid amplification of cDNA ends; SPA-1, signal-induced proliferation-associated gene 1.
Introduction
Myelodysplastic syndromes (MDSs), chronic myeloproliferative diseases (CMPDs), and myelodysplastic/myeloproliferative diseases (MDS/MPDs) are 3 different, heterogeneous groups of clonal hematopoietic stem cell disorders that are distinguished by a combination of morphological, immunophenotypic, genetic, and clinical characteristics (1, 2). Both inefficient hematopoiesis, which causes cytopenia, and disordered (dysplastic) maturation of 1 or more myeloid cell lines are characteristic of MDSs (3). In contrast, CMPDs are characterized by efficient hematopoiesis, which results in increased numbers of granulocytes, red blood cells, and/ or platelets in peripheral blood (4); nonetheless,...