Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARα-mediated increase of type II transglutaminase

Laura Benedetti, Francesco Grignani, Bianca M. Scicchitano, Anton M. Jetten, Daniela Diverio, Francesco Lo Coco, Giuseppe Avvisati, Carlo Gambacorti-Passerini, Sergio Adamo, Arthur A. Levin, Pier Giuseppe Pelicci, Clara Nervi

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Abstract

All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t- RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15; 17) translocation and expressing the PML-RARα product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with the t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor β subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t- RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARα-selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RARα-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARα-dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARα gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RARα for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.

Original languageEnglish
Pages (from-to)1939-1950
Number of pages12
JournalBlood
Volume87
Issue number5
Publication statusPublished - Mar 1 1996

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Acute Promyelocytic Leukemia
Retinoids
Tretinoin
Growth
Genes
Cells
Cycloheximide
transglutaminase 2
Gene expression
Cell Line
U937 Cells
Modulation
Ligands
Myeloid Cells
Messenger RNA
Leukocytes
Up-Regulation
Therapeutics
Clone Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Benedetti, L., Grignani, F., Scicchitano, B. M., Jetten, A. M., Diverio, D., Lo Coco, F., ... Nervi, C. (1996). Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARα-mediated increase of type II transglutaminase. Blood, 87(5), 1939-1950.

Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARα-mediated increase of type II transglutaminase. / Benedetti, Laura; Grignani, Francesco; Scicchitano, Bianca M.; Jetten, Anton M.; Diverio, Daniela; Lo Coco, Francesco; Avvisati, Giuseppe; Gambacorti-Passerini, Carlo; Adamo, Sergio; Levin, Arthur A.; Pelicci, Pier Giuseppe; Nervi, Clara.

In: Blood, Vol. 87, No. 5, 01.03.1996, p. 1939-1950.

Research output: Contribution to journalArticle

Benedetti, L, Grignani, F, Scicchitano, BM, Jetten, AM, Diverio, D, Lo Coco, F, Avvisati, G, Gambacorti-Passerini, C, Adamo, S, Levin, AA, Pelicci, PG & Nervi, C 1996, 'Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARα-mediated increase of type II transglutaminase', Blood, vol. 87, no. 5, pp. 1939-1950.
Benedetti L, Grignani F, Scicchitano BM, Jetten AM, Diverio D, Lo Coco F et al. Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARα-mediated increase of type II transglutaminase. Blood. 1996 Mar 1;87(5):1939-1950.
Benedetti, Laura ; Grignani, Francesco ; Scicchitano, Bianca M. ; Jetten, Anton M. ; Diverio, Daniela ; Lo Coco, Francesco ; Avvisati, Giuseppe ; Gambacorti-Passerini, Carlo ; Adamo, Sergio ; Levin, Arthur A. ; Pelicci, Pier Giuseppe ; Nervi, Clara. / Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARα-mediated increase of type II transglutaminase. In: Blood. 1996 ; Vol. 87, No. 5. pp. 1939-1950.
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abstract = "All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t- RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15; 17) translocation and expressing the PML-RARα product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with the t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor β subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t- RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARα-selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RARα-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARα-dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARα gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RARα for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.",
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AU - Jetten, Anton M.

AU - Diverio, Daniela

AU - Lo Coco, Francesco

AU - Avvisati, Giuseppe

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AU - Nervi, Clara

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N2 - All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t- RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15; 17) translocation and expressing the PML-RARα product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with the t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor β subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t- RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARα-selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RARα-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARα-dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARα gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RARα for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.

AB - All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t- RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15; 17) translocation and expressing the PML-RARα product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with the t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor β subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t- RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARα-selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RARα-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARα-dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARα gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RARα for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.

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