Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in Bcr-Abl-induced murine chronic myelogenous leukemia-like disease, and forced coexpression of ICSBP inhibits Bcr-Abl-induced myeloproliferative disorder.
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of a hematopoietic stem cell. The majority of cases of CML are associated with the (9;22) chromosome translocation that generates the bcr-abl chimeric gene. Alpha interferon (IFN-alpha) treatment induces hematological remission and prolongs life in 75% of CML patients in the chronic phase. It has been shown that mice deficient in interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor family, manifest a CML-like syndrome. We have shown that expression of Bcr-Abl in bone marrow (BM) cells from 5-fluorouracil (5-FU)-treated mice by retroviral transduction efficiently induces a myeloproliferative disease in mice resembling human CML. To directly test whether icsbp can function as a tumor suppressor gene, we examined the effect of ICSBP on Bcr-Abl-induced CML-like disease using this murine model for CML. We found that expression of the ICSBP protein was significantly decreased in Bcr-Abl-induced CML-like disease. Forced coexpression of ICSBP inhibited the Bcr-Abl-induced colony formation of BM cells from 5-FU-treated mice in vitro and Bcr-Abl-induced CML-like disease in vivo. Interestingly, coexpression of ICSBP and Bcr-Abl induced a transient B-lymphoproliferative disorder in the murine model of Bcr-Abl-induced CML-like disease. Overexpression of ICSBP consistently promotes rather than inhibits Bcr-Abl-induced B lymphoproliferation in a murine model where BM cells from non-5-FU-treated donors were used, indicating that ICSBP has a specific antitumor activity toward myeloid neoplasms. We also found that overexpression of ICSBP negatively regulated normal hematopoiesis. These data provide direct evidence that ICSBP can act as a tumor suppressor that regulates normal and neoplastic proliferation of hematopoietic cells.
Hao
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Department of Biology, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts 02454-9110, USA.
Ren
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D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000473:pathology; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D003114:Colony-Forming Units Assay; D016384:Consensus Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D005472:Fluorouracil / Q000494:pharmacology; D016313:Genes, abl; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors; D007372:Interferons / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000517:prevention & control*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D014178:Translocation, Genetic; D000099185:Interferon Regulatory Factor-8
D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D005472:Fluorouracil; D050835:Interferon Regulatory Factors; D007372:Interferons; D012097:Repressor Proteins; D000099185:Interferon Regulatory Factor-8