tetracycline and Leukemia--Myeloid

Recent studies show that several Hox transcription factors are important for regulation of proliferation and differentiation in hematopoiesis. Among these is H0XA10, which is selectively expressed at high levels in the most primitive subpopulation of human CD34(+) bone marrow cells. When overexpressed, H0XA10 increases the proliferation of early progenitor cells and can lead to the development of myeloid leukemia. To study the effects of H0XA10 on primitive hematopoietic progenitors in more detail, transgenic mice were generated with regulatable H0XA10 expression. The transgenic mouse model, referred to as tetO-HOXA10, contains the H0XA10 gene controlled by a tetracycline-responsive element and a minimal promoter. Thus, the expression of H0XA10 is inducible and reversible depending on the absence or presence of tetracycline or its analog, doxycycline. A retroviral vector containing the tetracycline transactivator gene (tTA) was used to induce expression of the H0XA10 gene in bone marrow cells from the transgenic mice. Reverse transcription-polymerase chain reaction analysis confirmed regulatable H0XA10 expression in several transgenic lines. H0XA10 induction led to the formation of hematopoietic colonies containing blastlike cells and megakaryocytes. Moreover, the induction of H0XA10 resulted in significant proliferative advantage of primitive hematopoietic progenitors (spleen colony-forming units [CFU-S(12)]), which was reversible on withdrawal of induction. Activation of H0XA10 expression in tet0-H0XA10 mice will therefore govern proliferation of primitive myeloid progenitors in a regulated fashion. This novel animal model can be used to identify the target genes of HOXA10 and better clarify the specific role of HOXA10 in normal and malignant hematopoiesis.

Topics: Animals; Antigens, CD34; Bone Marrow Cells; Cell Division; DNA-Binding Proteins; Doxycycline; Gene Expression; Gene Expression Regulation; Genes, Homeobox; Genetic Vectors; Hematopoietic Stem Cells; Homeobox A10 Proteins; Homeodomain Proteins; Leukemia, Myeloid; Megakaryocytes; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Models, Animal; Response Elements; Retroviridae; Reverse Transcriptase Polymerase Chain Reaction; Tetracycline

Since the first description of the helper-free retrovirus vector by Mann et al. (1983), many improvements have been introduced to the system to increase titer, or to achieve better expression of the transduced genes in cells of different lineage. The typical form of recombinant retrovirus vector utilizes its 5' long terminal repeat (LTR) as a promoter unit for the transcription of the inserted gene(s), which allows only the constitutive expression of the inserted gene(s) in target cells. Although constitutive expression of the delivered gene(s) in target cells may be sufficient for some purposes, controlled expression of gene(s) in target cells or tissues would be favorable in many basic and clinical applications. To circumvent these problems, we developed a new retroviral vector that allows controlled expression of the inserted genes. With these new retroviral vectors, the expression level of the inserted genes can be controlled up to 200-fold in the presence of a minimum amount of tetracycline. We think these new retroviral vectors will be useful in regulating the expression of the genes delivered in vivo.

Topics: 3T3 Cells; Animals; Encephalomyocarditis virus; Gene Expression Regulation; Genes, Viral; Genetic Vectors; Granulocyte-Macrophage Colony-Stimulating Factor; Leukemia, Myeloid; Mice; Retroviridae; Tetracycline; Transfection; Tumor Cells, Cultured; Viral Structural Proteins; Virion; Virus Replication

Patients with ARF and haematological malignancy (excluding myeloma), presenting to a single unit over 10 years were analyzed to see if patients likely to benefit from intensive renal supportive therapy could be identified. 31 episodes of ARF were identified in 29 patients (mean age 51 +/- 2.9 yr): 19 were associated with acute leukaemia (13 AML, 6 ALL); 10 with lymphoma. Acute tubular necrosis (ATN) was identified as the cause of ARF in 26 cases, with sepsis (96%) and exposure to nephrotoxic drugs (88%), especially aminoglycosides, being the commonest precipitating factors. Toxic levels of the latter were commonly documented. Patient survival was 45%. Requirement for mechanical ventilation resulted in a universally fatal outcome; age greater than 55 yr and the presence of CNS symptoms or signs were also significantly associated with a poor outcome. Non-ATN causes (urate nephropathy or obstruction) carried a better prognosis. However, only 4 patients (14%) lived for more than 6 months following ARF. Thus, although a subgroup of patients more likely to benefit from treatment can be identified, the overall prognosis is poor and limited by that of the underlying disease. The potential benefit of avoiding nephrotoxic drugs, especially aminoglycosides, in these patients is highlighted by this study.

Topics: Acute Kidney Injury; Adolescent; Adult; Age Factors; Aged; Aminoglycosides; Cyclosporins; Female; Humans; Kidney Tubular Necrosis, Acute; Leukemia, Myeloid; Lymphoma; Male; Middle Aged; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Risk Factors; Tetracycline

Topics: Aged; Alkaline Phosphatase; Anemia; Blood Transfusion; Bone Marrow; Busulfan; Cytarabine; Female; Histocytochemistry; Humans; Leukemia, Myeloid; Leukocytes; Male; Middle Aged; Pneumonia; Purpura; Radiography; Sepsis; Splenomegaly; Staphylococcal Infections; Tetracycline; Thioguanine

Topics: Boron; Cell Line; Cells, Cultured; Conjunctiva; Endoplasmic Reticulum; Female; HeLa Cells; Humans; Leukemia, Myeloid; Lung; Microscopy, Fluorescence; Neoplasms; Tetracycline; Uterine Cervical Neoplasms

Topics: Bone Marrow; Child; Electrons; Kanamycin; Leukemia; Leukemia, Myeloid; Lupus Erythematosus, Systemic; Microscopy; Microscopy, Electron; Mycoplasma; Neoplasms; Neutralization Tests; Oncogenic Viruses; Sarcoma; Tetracycline; Tissue Culture Techniques; Virus Cultivation

Topics: Adrenal Cortex Hormones; Blood Cell Count; Blood Transfusion; Bone Marrow Examination; Eosinophils; Hemostatics; Humans; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mercaptopurine; Pathology; Tetracycline; Thrombin; Vitamin B Complex

Topics: Abnormalities, Drug-Induced; Blood Transfusion; Dental Enamel; Female; Humans; Infant; Infant, Newborn; Leukemia; Leukemia, Myeloid; Mercaptopurine; Prednisone; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Tetracycline; Tooth Discoloration; Tooth, Deciduous; Toxicology