Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA 1

Jing Fang, Garrett Rhyasen, Lyndsey Bolanos, Christopher Rasch, Melinda Varney, Mark Wunderlich, Susumu Goyama, Gerrit Jansen, Jacqueline Cloos, Carmela Rigolino, Agostino Cortelezzi, James C. Mulloy, Esther N. Oliva, Maria Cuzzola, Daniel T. Starczynowski

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Bortezomib (Velcade) is used widely for the treatment of various human cancers; however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that bortezomib induces proteasome-independent degradation of the TRAF6 protein, but not mRNA, in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of bortezomib due to down-regulation of the proteasomal subunit α-1 (PSMA1). To determine the molecular consequences of loss of TRAF6 in MDS/AML cells, in the present study, we applied gene-expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe herein novel mechanisms by which TRAF6 is regulated through bortezomib/ autophagy-mediated degradation and by which it alters MDS/AML sensitivity to bortezomib by controlling PSMA1 expression.

Original languageEnglish
Pages (from-to)858-867
Number of pages10
JournalBlood
Volume120
Issue number4
DOIs
Publication statusPublished - Jul 26 2012

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TNF Receptor-Associated Factor 6
Myelodysplastic Syndromes
Autophagy
Acute Myeloid Leukemia
Degradation
Myeloid Cells
Cells
Apoptosis
Cell Line
Bortezomib
Proteasome Inhibitors
Gene Expression Profiling
Proteasome Endopeptidase Complex
Cytotoxicity
RNA Interference
Gene expression
Small Interfering RNA
Proteolysis
Neoplasms

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA 1. / Fang, Jing; Rhyasen, Garrett; Bolanos, Lyndsey; Rasch, Christopher; Varney, Melinda; Wunderlich, Mark; Goyama, Susumu; Jansen, Gerrit; Cloos, Jacqueline; Rigolino, Carmela; Cortelezzi, Agostino; Mulloy, James C.; Oliva, Esther N.; Cuzzola, Maria; Starczynowski, Daniel T.

In: Blood, Vol. 120, No. 4, 26.07.2012, p. 858-867.

Research output: Contribution to journalArticle

Fang, J, Rhyasen, G, Bolanos, L, Rasch, C, Varney, M, Wunderlich, M, Goyama, S, Jansen, G, Cloos, J, Rigolino, C, Cortelezzi, A, Mulloy, JC, Oliva, EN, Cuzzola, M & Starczynowski, DT 2012, 'Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA 1', Blood, vol. 120, no. 4, pp. 858-867. https://doi.org/10.1182/blood-2012-02-407999
Fang, Jing ; Rhyasen, Garrett ; Bolanos, Lyndsey ; Rasch, Christopher ; Varney, Melinda ; Wunderlich, Mark ; Goyama, Susumu ; Jansen, Gerrit ; Cloos, Jacqueline ; Rigolino, Carmela ; Cortelezzi, Agostino ; Mulloy, James C. ; Oliva, Esther N. ; Cuzzola, Maria ; Starczynowski, Daniel T. / Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA 1. In: Blood. 2012 ; Vol. 120, No. 4. pp. 858-867.
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abstract = "Bortezomib (Velcade) is used widely for the treatment of various human cancers; however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that bortezomib induces proteasome-independent degradation of the TRAF6 protein, but not mRNA, in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of bortezomib due to down-regulation of the proteasomal subunit α-1 (PSMA1). To determine the molecular consequences of loss of TRAF6 in MDS/AML cells, in the present study, we applied gene-expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe herein novel mechanisms by which TRAF6 is regulated through bortezomib/ autophagy-mediated degradation and by which it alters MDS/AML sensitivity to bortezomib by controlling PSMA1 expression.",
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T1 - Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA 1

AU - Fang, Jing

AU - Rhyasen, Garrett

AU - Bolanos, Lyndsey

AU - Rasch, Christopher

AU - Varney, Melinda

AU - Wunderlich, Mark

AU - Goyama, Susumu

AU - Jansen, Gerrit

AU - Cloos, Jacqueline

AU - Rigolino, Carmela

AU - Cortelezzi, Agostino

AU - Mulloy, James C.

AU - Oliva, Esther N.

AU - Cuzzola, Maria

AU - Starczynowski, Daniel T.

PY - 2012/7/26

Y1 - 2012/7/26

N2 - Bortezomib (Velcade) is used widely for the treatment of various human cancers; however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that bortezomib induces proteasome-independent degradation of the TRAF6 protein, but not mRNA, in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of bortezomib due to down-regulation of the proteasomal subunit α-1 (PSMA1). To determine the molecular consequences of loss of TRAF6 in MDS/AML cells, in the present study, we applied gene-expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe herein novel mechanisms by which TRAF6 is regulated through bortezomib/ autophagy-mediated degradation and by which it alters MDS/AML sensitivity to bortezomib by controlling PSMA1 expression.

AB - Bortezomib (Velcade) is used widely for the treatment of various human cancers; however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that bortezomib induces proteasome-independent degradation of the TRAF6 protein, but not mRNA, in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of bortezomib due to down-regulation of the proteasomal subunit α-1 (PSMA1). To determine the molecular consequences of loss of TRAF6 in MDS/AML cells, in the present study, we applied gene-expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe herein novel mechanisms by which TRAF6 is regulated through bortezomib/ autophagy-mediated degradation and by which it alters MDS/AML sensitivity to bortezomib by controlling PSMA1 expression.

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