Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Patent
1996-01-26
1998-11-03
Walsh, Stephen
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
435 691, 435325, C12N 516
Patent
active
058307605
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to genetic engineering and particularly to hematopoietic cell lines bearing altered retinoic acid receptors.
BACKGROUND OF THE INVENTION
Abbreviations used herein include: APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; BFU-E, burst-forming unit-erythroid; CAT, chloramphenicol acetyltransferase; CFU-E, colony-forming unit-erythroid; CFU-GM, colony-forming unit-granulocyte/macrophage; Epo, erythropoietin; GM-CSF, granulocyte-macrophage colony stimulating factor; IL-3, interleukin-3; IL-6, interleukin-6; IL-7, interleukin-7; IL-11, interleukin-11; HS, horse serum; IgE R, immunoglobulin E receptor; RA, retinoic acid; RAR.alpha., retinoic acid receptor-.alpha.; RARs, retinoic acid receptors; RXR, retinoid X receptor; SCF, stem cell factor.
Retinoic acid (RA), the natural acidic derivative of vitamin A (retinol), is a critical molecule regulating growth and differentiation of a wide variety of cells. RA is thought to be centrally involved in epithelial differentiation (37; see the appended citations), plays a critical role as a tissue-specific morphogen during embryogenesis (50) and as a suppressor of malignant transformation of epithelial cells both in vitro (39) and in vivo (29). These diverse and complex biologic effects of RA are mediated through a number of closely related nuclear RA receptors (RARs) that are members of the steroid/thyroid hormone receptor superfamily and possess discrete DNA-binding and RA (ligand) binding domains (22).
The expression of RARs is widespread with RAR mRNA noted in most fetal and adult tissue (57). Unlike the steroid hormone receptors, the RA receptors as well as thyroid hormone receptors appear to be associated with chromatin and may be constitutively bound to cis-acting regulatory sequences in the absence of ligand (10, 35). Thus these receptors may have different regulatory roles in the absence and presence of ligand.
Several lines of indirect evidence suggest that RA and RA receptors may be involved in regulating the development of hematopoietic progenitors. For example, RA receptor mRNA (predominantly RAR.alpha.) is widely expressed in different hematopoietic cell types (18, 23, 34). Treatment of a human myeloid leukemia cell line HL-60 with all-trans retinoic acid (ATRA) induces these cells to undergo terminal neutrophilic differentiation, and this induction is directly mediated through RAR.alpha. (3, 8). In addition, human acute promyelocytic leukemia (APL) exhibits a specific 15:17 chromosome translocation involving RAR.alpha. which presumably results in the disruption of a normal, albeit unknown, regulatory function of this particular RA receptor (1, 2, 20, 21, 32). Furthermore, ATRA induces the leukemia cells from APL patients to differentiate into mature neutrophils both in vitro and in vivo (4, 5, 30, 55). However, it is currently unknown if RA and RA receptors might also be involved in regulating normal hematopoietic differentiation.
Normal hematopoietic differentiation involves a single primitive stem cell that gives rise to all the other types of hematopoietic cells. The existence of a common pluripotential stem cell that is the progenitor of all lymphoid, myeloid, and erythroid cells was initially demonstrated by transplantation experiments using bone marrow cells carrying X-ray-induced chromosomal markers (55a). More recently, direct marking of bone marrow cells with retroviral vectors has further confirmed the existence of a common lympho-hematopoietic progenitor cell (36a). Through a combination of physical and immunological purification methods, the murine lympho-hematopoietic progenitor cells have been purified to near homogeneity (47a). Their frequency is estimated to be only 0.01-0.005% of all nucleated cells in the bone marrow. The scarcity of the lympho-hematopoietic stem cells and the difficulty in their purification and maintenance have hampered efforts to purify appreciable numbers of these cells. If such cells were available as continuous cell lines, they could be used to dissect
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Collins Steven J.
Tsai Schickwann
Fred Hutchinson Cancer Research Center
Pak Michael D.
Walsh Stephen
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