Erythroleukemia cells differentiation

Included among other differentiating cell lines which have been established in culture, is the human promyelocytic cell line HL-60, which differentiates into more mature myeloid cells upon treatment with retinoic acid and prostaglandin E] (PGEi). Friend erythroleukemia cells differentiate into hemoglobin-producing cells when treated with either dimethyl sulfoxide, or hexamethylene bis-acetamide. 

One of the first HDAC inhibitors to be identified and characterized was sodium butyrate, where it was found to alter the histone acetylation state (Riggs et al, 1977), and further determined to inhibit HDAC activity both in vitro and in vivo (Candido et al, 1978). Almost a decade later trichostatin A (TSA), a fungistatic antibiotic, was found to induce murine erythroleukemia cell differentiation (Yoshida et al, 1987). To date, a wide range of molecules have been described that inhibit the activity of Class I and Class II HDAC enzymes, and with a few exceptions, can be divided into structural classes including (1) small-molecule hydroxamates, such as TSA, suberoylanilide hydroxamic acid (SAHA), scriptaid and oxamflatin (2) short-chain fatty-acids, such as sodium butyrate, sodium phenylbutyrate and valproic acid (VPA) (3) cyclic tetrapeptides, such as apicidin, trapoxin and the depsipeptide FK-228 and (4) benzamides, such as MS-275 and Cl-994 (for reviews see Remiszewski et al, 2002 Miller et al, 2003). Some of these molecules are represented in Fig. 4. 

Nagai T, Igarashi K, Akasaka J, Fu-ruyama K, Fujita H, et al. 1998. Regulation of NF-E2 activity in erythroleukemia cell differentiation. J. Biol. Chem. 273 5358-65... 

HMG protein-induce erythroleukemia cell differentiation. Friend virus-induced mouse erythroleukemia cells differentiate under the effects of hexamethylene bisacetamide (HMBA) and HMGl protein. Ca" " ionophore induced excess HMGl protein and promoted leukemia cell differentiation. Further inducers of leukemia cell differentiation are HDAC inhibitors h)q)eracetylating N-terminal tails of core histones H3/4 (trichostatin), DMSO, phorbol myristate acetate (PMA), the activator of PKC. ... 

Sugiura M, Fram R, Munroe D, Kufe D (1984) DNA strand scission and ADP-ribosyltransferase activity during murine erythroleukemia cell differentiation. Dev Biol 104 484-488... 

Sistonen, L., Sarge, K.D., Phillips, B., Abravaya, K., Morimoto, R.I. (1992). Activation of heat shock factor 2 during hemin-induced differentiation of human erythroleukemia cells. Mol. Cell. Biol. 12,4104-4111. 

Yoshida M, Nomura S, Beppu T (1987) Effects of trichostatins on differentiation of murine erythroleukemia cells. Cancer Res 47(14) 3688-3691 Yoshida M, Kijima M, Akita M, Beppu T (1990) Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265(28) 17174-17179 Yu ZX, Li SH, Nguyen HP, Li XJ (2002) Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice. Hum Mol Genet 11(8) 905-914. 

Yoshida M, Nomura S, Beppu T. (1987) Effects of trichostatins on differentiation of murine erythroleukemia cells. Cancer Res 47 3688-3691. 

A EXPERIMENTAL FIGURE 9-27 Northern blot analysis reveals increased expression of f-globin mRNA in differentiated erythroleukemia cells. The total mRNA in extracts of erythroleukemia cells that were growing but uninduced and in cells induced to stop growing and allowed to differentiate for 48 hours or 96 hours was analyzed by Northern blotting for (J-globin mRNA. The density of a band is proportional to the amount of mRNA present. The (3-globin mRNA is barely detectable in uninduced cells (UN lane) but increases more than 1000-fold by 96 hours after differentiation is induced. [Courtesy of L. Kole.l... 

H. Fujita, M. Yamamoto, T. Yamagami, N. Hayashi, T.R. Bishop, H. De Verneuil, T. Yoshinaga, S. Shibahara, R. Morimoto, S. Sassa (1991). Sequential activation of genes for heme pathway enzymes during erythroid differentiation of mouse Friend virus-transformed erythroleukemia cells, Biochem. Biophys. Acta, 1090, 311-316. 

Terada M, Nudel U, Fibach E, Rifkind RA, Marks PA (1978) Changes in DNA associated with induction of differentiation by dimethyl sulfoxide in murine erythroleukemia cells. Cancer Res 38 835-840... 

Friend et al. [1] made the striking observation that dimethyl sulfoxide (DMSO)-treated Friend erythroleukemia cells (FEE) differentiate in vitro. Subsequently, a number of other chemicals, including butyric acid,hypoxanthine andhexamethylene bis-acetamide were shown to induce Friend cells [2], These inducers appear to remove a block in the differentiation process but the mechanisms involved are unknown. The finding that benzamide and nicotinamide induced Friend cells [3, 4] suggested that since both compounds were inhibitors of poly(ADP-ribose) polymerase, poly(ADP-ribosylation) may have a role in the differentiation process. Furthermore, since poly(ADP-ribose) polymerase requires DNA strand breaks for activity [5], these observations implicated DNA strand breaks in FEE differentiation. 

Niacin Analogs That Induce Differentiation of Friend Erythroleukemia Cells are Able to Cause DNA Hypomethylation... 

Friend erythroleukemia cells (FELCs) are retroviras-transformed murine leukemia cells of the erythroid lineage, blocked in a relatively early stage of differentiation (1). These cells can be induced to differentiate into erythroid-like cells able to synthesize hemoglobin mRNA, heme, and hemoglobin (Hb) (2, 3). Nicotinamide (NAm), a potent inhibitor of poly(ADP-ribose) synthetase, has been shown to be a moderate inducer of FELCs differentiation (4). Other inhibitors of poly(ADP-ribose) synthetase were also found to be capable of inducing differentiation (5). These investigations hypothesized that the inhibition of poly(ADP-ribose) turnover was the primary biochemical mechanism leading to differentiation of FELCs by NAm and related compounds. 

Kinoshita, T., U. Sankawa, T. Takuma, K. Asahi, and N. Takahashi Induction of Differentiation in Murine Erythroleukemia Cells by Flavonoids. Chem. Pharm. Bull. (Japan), 33, 4109 (1985). 

BREYER, I. AZZl, A. 2001. Differential inhibition by alpha- and beta-tocopherol of human erythroleukemia cell adhesion Role of integrins. Free Radio Biol Med, 30, 1381-9. 

A report by Garg and Brown (1983) shows that retinoids can also promote differentiation of certain cell lines of Friend erythroleukemia cells, inducing cells to synthesize hemoglobin and to increase acetylcholinesterase activity analogous to the response of the cells to the classic inducer dimethyl sulfoxide. Not all Friend leukemic cell lines respond to retinoic acid (Breitman et al., 1980b Garg... 

Hsu B 1982 The influence of several anticancer agents on cell proliferation, differentiation and the cell cycle of murine erythroleukemia cells. Am J Chin Med 9 268-276... 

Preisler, H.D. and Lyman, G., Differentiation of erythroleukemia cells in vitro — properties of chemical inducers. Cell Differ., 4,179,1975. 

Dell Aquila, M.L., H.T. Nguyen, C.L. Herald, G.R. Pettit, and P.M. Blumberg Inhibition by Bryostatin 1 of the Phorbol Ester-induced Blockage of Differentiation in Hexamethylene Bisacetamide-treated Friend Erythroleukemia Cells. Cancer Res. 47, 6006 (1987). 

Gascoyne, P. Pethig, R. Burt, J. and Becker, F. (1993), Membrane changes accompanying the induced differentiation of Friend murine erythroleukemia cells studied by dielectrophoresis, Biochimica et biophysica acta. Biomembranes 1149(1), 119—126. 

A particularly useful system for studies of cell differentiation was found to be murine erythroleukemia cells (Marks and Rifkind, 1978). These proerythroblasts, transformed by the Friend virus complex, can be permanently grown in a cell culture. Exposure to dimethylsulphoxide or a variety of other inducers stimulates MEL cells to make a transition to the more advanced stages of erythroid maturation. An analysis of the differentiated state of individual cells, based on cloning cells in a semi-solid medium, has revealed (Housman et al., 1978) that an irreversible commitment to differentiation occurs as a discrete event at a given time after the application of the inducer. Removal of the inducer prior to this event returns a cell to its initial state, whereas its removal after this event leaves it in the differentiated state. 

Housman, D., Gusella, J., Geller, R., Levenson, R., and Weil, S., 1978, Differentiation of murine erythroleukemia cells The central role of the commitment event, "Cold Spring Harbor... 

Fibach, E. Nahas, N. Giloh, H. Gatt, S. Uptake of fluorescent fatty acids by erythroleukemia cells. Effect of differentiation. Exp. Cell Res. 1986, 166, 220-228. 

Trichostatin (Fig. 17) was the first HDAC inhibitor discovered and one of the first two compounds (SAHA being the other) to enter clinical trials. Trichostatin (TSA) was first isolated in 1976, by Tsuji and Kobayashi from Streptomyces hygroscopicus as an antifungal antibiotic against Trichophyton spp. In the 1980s, it demonstrated the ability to induce differentiation in Friend murine erythroleukemia (MEL) cells and inhibited proliferation. ... 

In the same year, m-carboxycinnamic acid bishydroxamide (CBHA) and suberoylanihde hydroxamic acid (SAHA) were identified as inducers of terminal differentiation of murine erythroleukemia (MEL) cells (Fig. 4) [45]. It was not until two years later, however, that the HDACl and HDAC3 inhibiting capacities of these compoimds were recognized [46]. SAHA is currently the leading compoimd in the clinic, and is undergoing phase III chnical trials for the treatment of cutaneous T cell lymphoma (CTCL). 

Murray NR, Baumgardner GP, Burns DJ, Fields AP (1993) Protein kinase C isotypes in human erythroleukemia (K562) cell proliferation and differentiation. Evidence that beta II protein kinase C is required for proliferation. J Biol Chem 268 15847-15853... 

BA is a potent differentiation agent in a wide variety of cancer cells in-vivo and in-vitro [23, 24]. Butyrate has been shown to specifically affect genes regulation by transcriptional and post transcriptional modifications. It induces dose dependent differentiation and inhibits proliferation of various malignant cells types including erythroleukemia, embryonal carcinoma and colon carcinoma [25, 26]. BA induced the expression of specific differentiation-associated genes when used at concentration between 0.5-10 mM. Differentiated cells are characterized by appearance of regulatory enzymes such as alkaline phosphatase [27]. 

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