All-Trans-Retinoic-Acid- and Growth-Factor- Mediated Induction of Alkaline Phosphatase Activity in Freshly Isolated Chronic Myeloid Leukemia Cells

1999 ◽  
Vol 102 (2) ◽  
pp. 61-65 ◽  
Author(s):  
Fabio Stagno ◽  
Patrizia Guglielmo ◽  
Ugo Consoli ◽  
Paolo Fiumara ◽  
Giuseppe S.A. Longo ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Retinoic Acid ◽  
Growth Factor ◽  
Chronic Myeloid Leukemia ◽  
Phosphatase Activity ◽  
Alkaline Phosphatase Activity ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Olfactomedin 4 Mediates All-Trans Retinoic Acid Induced Growth Inhibition, Differentiation and Apoptosis in Myeloid Leukemia Cells and Inhibits 4E-BP1 Phosphorylation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2395-2395
Author(s):  
Wenli Liu ◽  
Hyun W Lee ◽  
Griffin P Rodgers
Keyword(s):  
Retinoic Acid ◽  
Chronic Myeloid Leukemia ◽  
Growth Inhibition ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Over Expression ◽  
Retinoic Acids ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Novel Target

Abstract Abstract 2395 Poster Board II-372 Introduction: All-trans retinoic acid (ATRA) has been shown to induce cellular differentiation and growth inhibition of acute promyelocytic leukemia cells. Clinical application of ATRA has proved extremely successful in inducing clinical remission in most acute promyelocytic leukemia patients. Although the mechanisms of retinoid-dependent gene transcription regulation are well understood, the target genes that mediate retinoid-induced biological responses still remain to be defined. Olfactomedin 4 (OLFM4, also called hGC-1 and GW112) is a member of olfactomedin-related glycoprotein family. It is constitutively expressed in myeloid cells and gastrointestinal tract. It has been recently reported that OLFM4 expression is up-regulated in stomach and colon cancer patients. The purpose of this study is to examine its expression in myeloid leukemia patients, its regulation by ATRA and potential biological functions in myeloid leukemia. Results: 1) In this study, we found that OLFM4 expression was up-regulated in the peripheral leukocytes of chronic myeloid leukemia patients (91%, 22 cases) and acute myeloid leukemia patients (30%, 10 cases). OLFM4 expression in accelerated phase of chronic myeloid leukemia patients was significantly higher than that in chronic phase. 2) We identified that OLFM4 is a novel target gene of retinoic acids in myeloid leukemia cells. Treatment of HL-60 cells with ATRA and 9-cis-RA induced OLFM4 expression. The expression level of OLFM4 is correlated with the myeloid cell differentiation stage. Deletion analysis led to the identification of a positive retinoic acid response element (DR5) and a negative response element (DR1) within OLFM4 promoter. Furthermore, electrophoretic mobility-shift assays and transfection study in COS-7 cells demonstrated that RARα/RXRα binds to the DR5 site and mediates ATRA induced transactivation of OLFM4 promoter. 3) We showed that OLFM4 over-expression in HL-60 cells lead to growth inhibition, differentiation and apoptosis and potentates ATRA mediated these effects. Conversely, silencing of endogenous OLFM4 by lentiviral shRNA against OLFM4 in AML-193 cells reduces ATRA induced growth inhibition, differentiation and apoptosis. 4) We further investigated the molecular mechanism that OLFM4 is involved in leukemia cell growth and differentiation. We found that over-expression of OLFM4 in HL60 cells inhibited ATRA induced phosphorylation of translation repressor 4E-BP1. This inhibitory effect was further confirmed in 293T cells, in which over-expression of OLFM4 inhibits 4E-BP1 phosphorylation at all four phosphorylation sites (Thr37/46, Thr70 and Ser65). Application of lentiviral shRNA against OLFM4 in AML-193 increased phosphorylation of 4E-BP1 compared with control shRNA. Over-expression of OLFM4 in HL60 cells does not affect phosphorylation of Akt, p70S6 kinase, GSK3β and ERK1/2 . Conclusion: 1) OLFM4 expression is up-regulated in chronic and acute myeloid leukemia patients and is correlated with the stage of chronic myeloid leukemia. 2) OLFM4 is a novel target gene of retinoic acids. RARα/RXRα binds to the DR5 site of OLFM4 promoter and mediates the ATRA induced transactivation of OLFM4. 3) OLFM4 mediates ATRA induced growth inhibition, differentiation and apoptosis of myeloid leukemia cells. 4) OLFM4 acts an inhibitor of 4E-BP1 phosphorylation down stream of Akt and mTOR, suggesting OLFM4 may inhibit protein synthesis that is observed with the differentiation of myeloid leukemia cells. Our results suggest that OLFM4 up-regulation in the leukocytes of leukemia patients might have a feedback effect to restrain cell growth, and induce differentiation and apoptosis rather than act as an initiator of leukemiagenesis. As OLFM4 is a secreted glycoprotein, it could represent a promising therapeutic agent in the treatment of myeloid leukemia patients. The effect of purified OLFM4 on leukemia cells is currently under investigation. Disclosures: No relevant conflicts of interest to declare.

Induction of alkaline phosphatase activity in chronic myeloid leukemia cells: In vitro studies and speculative hypotheses

1990 ◽  
Vol 35 (4) ◽  
pp. 278-280 ◽  
Author(s):  
A. De Renzo ◽  
V. Micera ◽  
S. Vaglio ◽  
L. Luciano ◽  
C. Selleri ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Chronic Myeloid Leukemia ◽  
Phosphatase Activity ◽  
Alkaline Phosphatase Activity ◽  
Myeloid Leukemia ◽  
In Vitro Studies ◽  
Leukemia Cells

In vitro Apoptotic Response of Freshly Isolated Chronic Myeloid Leukemia Cells to all-trans Retinoic Acid and Cytosine Arabinoside

2000 ◽  
Vol 104 (2-3) ◽  
pp. 57-64 ◽  
Author(s):  
Fabio Stagno ◽  
Patrizia Guglielmo ◽  
Ugo Consoli ◽  
Giovanna Inghilterra ◽  
Giada Maria Giustolisi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Chronic Myeloid Leukemia ◽  
Cytosine Arabinoside ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Apoptotic Response ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in the chronic phase

Leukemia ◽  
1998 ◽  
Vol 12 (4) ◽  
pp. 449-454 ◽  
Author(s):  
D Russo ◽  
M Regazzi ◽  
S Sacchi ◽  
G Visani ◽  
M Lazzarino ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Trans Retinoic Acid ◽  
All Trans 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

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.

scholarly journals All-trans retinoic acid potentiates the inhibitory effects of interferon α on chronic myeloid leukemia progenitors in vitro

Leukemia ◽  
1997 ◽  
Vol 11 (5) ◽  
pp. 667-673 ◽  
Author(s):  
FX Mahon ◽  
H Chahine ◽  
C Barbot ◽  
V Pigeonnier ◽  
B Jazwiec ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Interferon Α ◽  
Inhibitory Effects ◽  
Trans Retinoic Acid ◽  
All Trans 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.

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