5 results on '"Kogan, S. C."'
Search Results
2. BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia.
- Author
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Kogan SC, Brown DE, Shultz DB, Truong BT, Lallemand-Breitenbach V, Guillemin MC, Lagasse E, Weissman IL, and Bishop JM
- Subjects
- Animals, Antigens, Differentiation genetics, Apoptosis genetics, Bone Marrow Cells cytology, Calcium-Binding Proteins genetics, Calgranulin A, Cell Differentiation, Cell Division, Cell Transformation, Neoplastic, Chromosome Aberrations, Chromosome Disorders, Hematopoietic Stem Cells, Leukemia, Promyelocytic, Acute mortality, Leukemia, Promyelocytic, Acute pathology, Leukopoiesis, Mice, Mice, Transgenic, Myeloid Cells cytology, Recombinant Fusion Proteins metabolism, Leukemia, Promyelocytic, Acute etiology, Neoplasm Proteins metabolism, Neutrophils cytology, Oncogene Proteins, Fusion metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism
- Abstract
The promyelocytic leukemia retinoic acid receptor alpha (PMLRARalpha) chimeric protein is associated with acute promyelocytic leukemia (APL). PMLRARalpha transgenic mice develop leukemia only after several months, suggesting that PMLRARalpha does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRARalpha to initiate leukemia. Evaluation of preleukemic animals showed that whereas PMLRARalpha alone modestly altered neutrophil maturation, the combination of PMLRARalpha and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRARalpha and BCL-2 than in mice expressing PMLRARalpha alone, and all mice expressing both transgenes succumbed to leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRARalpha to initiate APL. more...
- Published
- 2001
- Full Text
- View/download PDF
Catalog
3. Leukemia initiated by PMLRARalpha: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable.
- Author
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Kogan SC, Hong SH, Shultz DB, Privalsky ML, and Bishop JM
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Differentiation drug effects, Chlorocebus aethiops, Disease Progression, Genes, Dominant, Humans, Leukemia, Experimental drug therapy, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute pathology, Mice, Mice, Transgenic, Mutagenesis, Neoplasm Proteins physiology, Oncogene Proteins, Fusion physiology, Phenotype, Protein Structure, Tertiary, Radiation Chimera, Recombinant Fusion Proteins physiology, Repressor Proteins physiology, Transfection, Tretinoin therapeutic use, Cell Transformation, Neoplastic genetics, Gene Expression Regulation, Leukemic drug effects, Leukemia, Experimental genetics, Leukemia, Promyelocytic, Acute metabolism, Neoplasm Proteins chemistry, Oncogene Proteins, Fusion chemistry, Transcriptional Activation drug effects, Tretinoin pharmacology
- Abstract
The most common chromosomal translocation in acute promyelocytic leukemia (APL), t15;17(q22;q21), creates PMLRARalpha and RARalphaPML fusion genes. We previously developed a mouse model of APL by expressing PMLRARalpha in murine myeloid cells. In order to examine the mechanisms by which PMLRARalpha can initiate leukemia, we have now generated transgenic mice expressing PMLRARalpham4 and RARalpham4, proteins that are unable to activate transcription in response to retinoic acid. PMLRARalpham4 transgenic mice developed myeloid leukemia, demonstrating that transcriptional activation by PMLRARalpha is not required for leukemic transformation. The characteristics of the leukemias arising in the PMLRARalpham4 transgenic mice varied from those previously observed in our PMLRARalpha transgenic mice, indicating that ligand responsiveness may influence the phenotype of the leukemic cells. The leukemias that arose in PMLRARalpham4 transgenic mice did not differentiate in response to retinoic acid therapy. This result supports the hypothesis that a major therapeutic effect of retinoic acid is mediated directly through the PMLRARalpha protein. However, a variable effect on survival suggested that this agent may be of some benefit in APL even when leukemic cells are resistant to its differentiative effects. Transgenic mice expressing high levels of RARalpham4 have not developed leukemia, providing evidence that the PML domain of PMLRARalpha plays a specific and critical role in the pathogenesis of APL. (Blood. 2000;95:1541-1550) more...
- Published
- 2000
4. Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia.
- Author
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Lallemand-Breitenbach V, Guillemin MC, Janin A, Daniel MT, Degos L, Kogan SC, Bishop JM, and de Thé H
- Subjects
- Animals, Apoptosis drug effects, Arsenic administration & dosage, Cell Differentiation drug effects, Drug Screening Assays, Antitumor, Drug Synergism, Hematopoiesis drug effects, Humans, Leukemia, Promyelocytic, Acute pathology, Liver pathology, Lung pathology, Mice, Mice, Transgenic, Neoplasm Transplantation, Neoplastic Stem Cells drug effects, Remission Induction, Spleen pathology, Tretinoin administration & dosage, Tumor Cells, Cultured, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arsenic pharmacology, Leukemia, Promyelocytic, Acute drug therapy, Neoplasm Proteins metabolism, Oncogene Proteins, Fusion metabolism, Tretinoin pharmacology
- Abstract
In acute promyelocytic leukemia (APL) patients, retinoic acid (RA) triggers differentiation while arsenic trioxide (arsenic) induces both a partial differentiation and apoptosis. Although their mechanisms of action are believed to be distinct, these two drugs both induce the catabolism of the oncogenic promyelocytic leukemia (PML)/RARalpha fusion protein. While APL cell lines resistant to one agent are sensitive to the other, the benefit of combining RA and arsenic in cell culture is controversial, and thus far, no data are available in patients. Using syngenic grafts of leukemic blasts from PML/RARalpha transgenic mice as a model for APL, we demonstrate that arsenic induces apoptosis and modest differentiation, and prolongs mouse survival. Furthermore, combining arsenic with RA accelerates tumor regression through enhanced differentiation and apoptosis. Although RA or arsenic alone only prolongs survival two- to threefold, associating the two drugs leads to tumor clearance after a 9-mo relapse-free period. These studies establishing RA/arsenic synergy in vivo prompt the use of combined arsenic/RA treatments in APL patients and exemplify how mouse models of human leukemia can be used to design or optimize therapies. more...
- Published
- 1999
- Full Text
- View/download PDF
5. The PEBP2betaMYH11 fusion created by Inv(16)(p13;q22) in myeloid leukemia impairs neutrophil maturation and contributes to granulocytic dysplasia.
- Author
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Kogan SC, Lagasse E, Atwater S, Bae SC, Weissman I, Ito Y, and Bishop JM
- Subjects
- Animals, Cell Differentiation, DNA-Binding Proteins physiology, Gene Expression, Granulocytes pathology, Hematopoiesis genetics, Humans, Leukemia, Myeloid, Acute pathology, Leukocyte Count, Mice, Mice, Transgenic, Myelodysplastic Syndromes etiology, Myelodysplastic Syndromes genetics, Oncogene Proteins, Fusion physiology, Transcription Factor AP-2, Transcription Factors physiology, Chromosome Inversion, Chromosomes, Human, Pair 16 genetics, DNA-Binding Proteins genetics, Leukemia, Myeloid, Acute genetics, Neutrophils pathology, Oncogene Proteins, Fusion genetics, Transcription Factors genetics
- Abstract
Chromosomal translocations involving the genes encoding the alpha and beta subunits of the Pebp2/Cbf transcription factor have been associated with human acute myeloid leukemia and the preleukemic condition, myelodysplasia. Inv(16)(p13;q22) fuses the gene encoding the beta subunit of Pebp2 to the MYH11 gene encoding a smooth muscle myosin heavy chain (Smmhc). To examine the effect of the inv(16)(p13;q22) on myelopoiesis, we used the hMRP8 promoter element to generate transgenic mice expressing the Pebp2betaSmmhc chimeric fusion protein in myeloid cells. Neutrophil maturation was impaired in PEBP2betaMYH11 transgenic mice. Although the transgenic mice had normal numbers of circulating neutrophils, their bone marrow contained increased numbers of immature neutrophilic cells, which exhibited abnormal characteristics. In addition, PEBP2betaMYH11 inhibited neutrophilic differentiation in colonies derived from hematopoietic progenitors. Coexpression of both PEBP2betaMYH11 and activated NRAS induced a more severe phenotype characterized by abnormal nuclear morphology indicative of granulocytic dysplasia. These results show that PEBP2betaMYH11 can impair neutrophil development and provide evidence that alterations of Pebp2 can contribute to the genesis of myelodysplasia. more...
- Published
- 1998
- Full Text
- View/download PDF
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