Tumor Necrosis Factor-a Enhances Human Leukemia Cell Differentiation Induced by DMSO, but Not Retinoic Acid.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3893-3893
Author(s):  
Hong-Nu Yu ◽  
Young-Rae Lee ◽  
Hyun-Jaung Shim ◽  
Myung-Kwan Han ◽  
Eun-Kyung Song ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Tumor Necrosis ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Induced Differentiation ◽  
Cd11b Expression ◽  
Hl60 Cells ◽  
Reducing Activity ◽  
Necrosis Factor

Abstract One of the human leukemia treatment methods is to differentiate leukemia cells into mature cells. Because differentiated cells lose their proliferative and tumor-forming abilities, differentiation inducers may be useful for the treatment of leukemia. Differentiation of leukemia cells has been studied using HL60 cells, a human promyelocytic leukemia cell line, which can be differentiated into granulocyte-like or monocyte/macrophage-like cells by various pharmacological agents such as dimethyl sulfoxide (DMSO), retinoic acid and phorbol myristic acetate (PMA). We previously reported that nuclear factor - kB (NF-kB) activation plays the important role in DMSO-induced differentiation of HL60 cells. Thus, we hypothesized that NF-kB activators could enhance DMSO-induced differentiation of HL60 cells. Here we examine whether tumor necrosis factor-a (TNF-a), a potent NF-kB inducer, enhance DMSO-induced differentiation of HL60 cells. TNF-a was found to enhance HL60 cell differentiation induced by DMSO. CD11b, a differentiation marker, was increased in 0.5 % DMSO-treated cells compared to control cells. When TNF-a was added to the same condition, CD11b expression was further enhanced in a dose and a time dependent manners. We also found that nitro blue tetrazolium (NBT) reducing activity, a marker for granulocytic differentiation, was further increased in DMSO plus TNF-a treated cells compared to only DMSO- treated cells. However, TNF-a alone had no effect on CD11b expression and NBT reducing activity. The enhancement of DMSO-induced HL60 differentiation by TNF-a was offset by NF-kB inhibition. Interestingly, retinoic acid- induced differentiation of HL60 cells showed no enhancing effect of TNF--a on the differentiation. These findings indicate that TNF--a might affect only NF-kB dependent differentation of HL60 cells. Taken together, we demonstrated that TNF-a enhances DMSO-induced differentiation of HL60 cells by stimulating NF-kB activation. Our results suggest that NF-kB inducers such as TNF-a are useful for the treatment of leukemia in combination with DMSO.

scholarly journals Regulation of myeloblastin messenger RNA expression in myeloid leukemia cells treated with all-trans retinoic acid

Blood ◽  
1993 ◽  
Vol 81 (2) ◽  
pp. 475-481 ◽  
Author(s):  
C Labbaye ◽  
J Zhang ◽  
JL Casanova ◽  
M Lanotte ◽  
J Teng ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Mrna Expression ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Nb4 Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Retinoic acid is known to induce differentiation of human myeloid leukemia cells in vitro. Recently, all-trans retinoic acid has been used to induce remissions in patients with acute promyelocytic leukemia, probably through differentiation of the leukemia cells. Myeloblastin (mbn) is a protease that has been identified in the human leukemia cell line HL-60. Downregulation of this protease can inhibit proliferation and induce differentiation of HL-60-derived leukemia cells. Here we have investigated the regulation of mbn messenger RNA (mRNA) expression in two human leukemia cell lines, HL-60 and NB4, treated with all-trans retinoic acid. Under this treatment, downregulation of mbn mRNA was observed in both cell lines, but was considerably delayed in NB4 cells that carry the t(15;17) translocation characteristic of acute promyelocytic leukemia. We have found that multiple mechanisms were involved in the control of mbn mRNA expression. These mechanisms were different in HL-60 and NB4 cells. Our results show that in HL-60 cells, all-trans retinoic acid rapidly decreased transcription of mbn. In contrast, in the t(15;17)-positive NB4 cells treated with all-trans retinoic acid, upregulation of mbn mRNA expression was followed by a late downregulation, both achieved via posttranscriptional mechanisms.

Effects of Tumor Necrosis-Factor on Primary Human Leukemia Cells: Ultrastructural Changes

1993 ◽  
Vol 90 (2) ◽  
pp. 77-83 ◽  
Author(s):  
R. Munker ◽  
L. Greither ◽  
M. Darsow ◽  
J.W. Ellwart ◽  
R. Mailhammer ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leukemia Cells ◽  
Ultrastructural Changes ◽  
Human Leukemia ◽  
Human Leukemia Cells ◽  
Necrosis Factor

Expression of retinoic acid receptor alpha mRNA in human leukemia cells

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 99-102 ◽  
Author(s):  
C Largman ◽  
K Detmer ◽  
JC Corral ◽  
FM Hack ◽  
HJ Lawrence
Keyword(s):  
Retinoic Acid ◽  
Cell Lines ◽  
Retinoic Acid Receptor ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Retinoic Acid Receptor Alpha ◽  
Acid Receptor ◽  
Receptor Alpha ◽  
Human Leukemia Cells

The expression of the newly described human retinoic acid receptor alpha (RAR alpha) in six nonlymphoid and six lymphoid leukemia cell lines and nine freshly obtained samples of leukemia cells from patients with acute nonlymphoid leukemia was assessed by Northern blot analysis, using a full length cDNA clone of RAR alpha as probe. RAR alpha was expressed in all 12 cell lines and in all fresh leukemia samples as two major transcripts of 2.6 and 3.5 kb in size. Levels of RAR alpha expression and transcript sizes in retinoid-sensitive cells (such as HL60 or fresh promyelocytic leukemia cells) were not different from those in other samples. Moreover, expression of RAR alpha was not significantly modulated by exposure to cis-retinoic acid (cisRA) in either cisRA-responsive or unresponsive cells. By using a 3′ fragment of the RAR alpha gene as a probe, we confirmed that the transcripts visualized did not represent the homologous RAR beta gene. RAR alpha appears to be expressed in most human leukemia cells regardless of the type of biologic response to retinoic acid.

scholarly journals Regulation of myeloblastin messenger RNA expression in myeloid leukemia cells treated with all-trans retinoic acid

Blood ◽  
1993 ◽  
Vol 81 (2) ◽  
pp. 475-481 ◽  
Author(s):  
C Labbaye ◽  
J Zhang ◽  
JL Casanova ◽  
M Lanotte ◽  
J Teng ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Mrna Expression ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Nb4 Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Retinoic acid is known to induce differentiation of human myeloid leukemia cells in vitro. Recently, all-trans retinoic acid has been used to induce remissions in patients with acute promyelocytic leukemia, probably through differentiation of the leukemia cells. Myeloblastin (mbn) is a protease that has been identified in the human leukemia cell line HL-60. Downregulation of this protease can inhibit proliferation and induce differentiation of HL-60-derived leukemia cells. Here we have investigated the regulation of mbn messenger RNA (mRNA) expression in two human leukemia cell lines, HL-60 and NB4, treated with all-trans retinoic acid. Under this treatment, downregulation of mbn mRNA was observed in both cell lines, but was considerably delayed in NB4 cells that carry the t(15;17) translocation characteristic of acute promyelocytic leukemia. We have found that multiple mechanisms were involved in the control of mbn mRNA expression. These mechanisms were different in HL-60 and NB4 cells. Our results show that in HL-60 cells, all-trans retinoic acid rapidly decreased transcription of mbn. In contrast, in the t(15;17)-positive NB4 cells treated with all-trans retinoic acid, upregulation of mbn mRNA expression was followed by a late downregulation, both achieved via posttranscriptional mechanisms.

Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3335-3342 ◽  
Author(s):  
Michael Witcher ◽  
Hoi Ying Shiu ◽  
Qi Guo ◽  
Wilson H. Miller
Keyword(s):  
Retinoic Acid ◽  
Tumor Necrosis Factor ◽  
Cell Line ◽  
Acute Promyelocytic Leukemia ◽  
Tumor Necrosis ◽  
Promyelocytic Leukemia ◽  
Leukemia Cells ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Necrosis Factor

Abstract Retinoic acid (RA) overcomes the maturation block in t(15:17) acute promyelocytic leukemia (APL), leading to granulocytic differentiation. Patients receiving RA alone invariably develop RA resistance. RA-resistant cells can serve as useful models for the development of treatments for both APL and other leukemias. Previously, we showed that RA and tumor necrosis factor (TNF) promote monocytic differentiation of the APL cell line NB4 and U937 monoblastic cells. Here, we report that combining TNF with RA leads to maturation of several RA-resistant APL cells along a monocytic pathway, whereas UF-1, a patient-derived RA-resistant cell line, showed characteristics of granulocytic differentiation. We found distinct differences in gene regulation between UF-1 cells and cells showing monocytic differentiation. Although IRF-7 was up-regulated by TNF and RA in all cells tested, expression of c-jun and PU.1 correlated with monocytic differentiation. Furthermore, synergistic induction of PU.1 DNA binding and macrophage colony-stimulating factor receptor (m-CSF-1R) mRNA was observed only in cells differentiating into monocytes. Using neutralizing antibodies against m-CSF-1R or its ligand, we found that inhibiting this pathway strongly reduced CD14 expression in response to RA and TNF, suggesting that this pathway is essential for their synergy in RA-resistant leukemia cells. (Blood. 2004;104:3335-3342)

scholarly journals Retinoic acid cooperates with tumor necrosis factor and immune interferon in inducing differentiation and growth inhibition of the human promyelocytic leukemic cell line HL-60

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1218-1224 ◽  
Author(s):  
G Trinchieri ◽  
M Rosen ◽  
B Perussia
Keyword(s):  
Retinoic Acid ◽  
Tumor Necrosis Factor ◽  
Cell Line ◽  
Tumor Necrosis ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Ifn Gamma ◽  
Immune Interferon ◽  
Hla Class I Antigens ◽  
Necrosis Factor

In this study, we analyzed the effect of tumor necrosis factor (TNF) on retinoic acid (RA)-induced myeloid differentiation of the promyelocytic HL-60 leukemia cell line. We show that low concentrations of the two substances, almost inactive in inducing differentiation when used separately, induce differentiation when added simultaneously to the cell cultures. Cells simultaneously expressing both monocyte/macrophage phenotype (typically induced by TNF) and granulocyte characteristics (typically induced by RA) are induced by a combination of the two factors, indicating that TNF and RA potentiate each other's activity. The results obtained using immune interferon (IFN-gamma) in combination with the two inducers suggest that the mechanism of action of TNF and IFN-gamma are possibly different. The inhibitory effect of RA on the expression of HLA class I antigens and of the high-affinity Fc receptor is potentiated by TNF but completely reversed by rIFN-gamma.

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