LONG NON-CODING RNA MALAT1 WAS ASSOCIATED WITH PROGRESSION OF MULTIPLE MYELOMA AND INDUCED BY CELLULAR STRESS
(Abstract release date: 05/19/16)
EHA Library. Handa H. 06/09/16; 132793; E1244
Dr. Hiroshi Handa
Contributions
Contributions
Abstract
Abstract: E1244
Type: Eposter Presentation
Background
Recent transcriptome-wide analyses have revealed an overwhelming amount of transcribed but not translated non-coding RNAs capable of influencing diverse cellular processes such as proliferation, apoptosis, and motility. Long non-coding RNA (lnc RNAs), which are commonly defined as transcripts >200 nt in length, have emerged as a class of key regulatory RNA. LncRNAs are deregulated in diverse human cancers and associated with disease progression; however little is available in multiple myeloma (MM).
Aims
To elucidate the role of lnc RNA in MM, we studied expression pattern of several well-known lnc RNAs in plasma cells of MM, MGUS and plasmacytoma, and function in MM cell lines in vitro. Moreover, to reveal the distinct lnc RNA signature more comprehensively, we performed next generation sequencing based RNA sequencing, which is potentially able to discover novel lnc RNAs.
Methods
Purified CD138+ plasma cells from bone marrow (BM) mononuclear cells obtained from 110 of MM patients, 48 of MGUS patients, 19 of control BM and 5 of extramedullary disease (EMD) are subjected to the study after obtaining informed consent. The expression levels of lnc RNAs were determined by RQ-PCR. RNase H-activating LNA™ GapmeR antisense oligonucleotides were used to knockdown lnc RNA in vitro in MM cell lines. The cell lines were treated with bortezomib, MG132, doxorubicin to evaluate the effects of cytotoxic stress for the lnc RNA expression. RNA sequencing was performed with Illumina NextSeq 500. This study was approved by IRB of Gunma University Hospital under Declaration of Helsinki.
Results
We found significant higher level of MALAT1 expression in BM plasma cells of MM compared to MGUS and control (control vs MM, p<0.001; control vs MGUS, p=0.01; MGUS vs MM, p<0.001). MALAT1 expression in EMD was higher by 140 fold than BM MM cells. MALAT1 expression was higher in MM with t(4;14) and del 17p (p=0.049, p=0.03), but was not different among ISS (p=0.87). Higher MALAT1 expression is associated shorter progression free survival (p<0.05), and tendency of shorter overall survival (p=0.09). MM cell lines KMS12PE, OPM2, KMS11 treated with bortezomib showed elevated MALAT1 expression by 4.3 -21.8 fold and ANRIL by 2.2-4.7 fold. Cytotoxic drug doxorubicin also elevated both lnc RNAs in the cell lines. MALAT1 knockdown by GapmeR did not affect cell proliferation. The reported cell motility genes HMMR, CTHRC1 and ROD1 did not alter in MALAT1 knockdown MM cell lines, but RNA sequencing revealed the changes of many gene expressions. Finally, RNA sequencing of MM, MGUS and EMD samples revealed distinct lnc RNA expression signature as well as protein coding genes.
Conclusion
Significant upregulations of lnc RNAs MALAT1 might be associated with MM progression. Given that MALAT1 is associated with lung cancer metastasis, MALAT1 might be strongly associated with EMD formation . Genotoxic and ER stress induced by therapeutic drugs might upregulate MALAT1 leading extramedullary extension. Revealing distinct lnc RNA signature of MM is current important issue to clarify molecular mechanisms underlying MM progression and to development novel therapies.
Session topic: E-poster
Keyword(s): Epigenetic, Multiple myeloma, Progression
Type: Eposter Presentation
Background
Recent transcriptome-wide analyses have revealed an overwhelming amount of transcribed but not translated non-coding RNAs capable of influencing diverse cellular processes such as proliferation, apoptosis, and motility. Long non-coding RNA (lnc RNAs), which are commonly defined as transcripts >200 nt in length, have emerged as a class of key regulatory RNA. LncRNAs are deregulated in diverse human cancers and associated with disease progression; however little is available in multiple myeloma (MM).
Aims
To elucidate the role of lnc RNA in MM, we studied expression pattern of several well-known lnc RNAs in plasma cells of MM, MGUS and plasmacytoma, and function in MM cell lines in vitro. Moreover, to reveal the distinct lnc RNA signature more comprehensively, we performed next generation sequencing based RNA sequencing, which is potentially able to discover novel lnc RNAs.
Methods
Purified CD138+ plasma cells from bone marrow (BM) mononuclear cells obtained from 110 of MM patients, 48 of MGUS patients, 19 of control BM and 5 of extramedullary disease (EMD) are subjected to the study after obtaining informed consent. The expression levels of lnc RNAs were determined by RQ-PCR. RNase H-activating LNA™ GapmeR antisense oligonucleotides were used to knockdown lnc RNA in vitro in MM cell lines. The cell lines were treated with bortezomib, MG132, doxorubicin to evaluate the effects of cytotoxic stress for the lnc RNA expression. RNA sequencing was performed with Illumina NextSeq 500. This study was approved by IRB of Gunma University Hospital under Declaration of Helsinki.
Results
We found significant higher level of MALAT1 expression in BM plasma cells of MM compared to MGUS and control (control vs MM, p<0.001; control vs MGUS, p=0.01; MGUS vs MM, p<0.001). MALAT1 expression in EMD was higher by 140 fold than BM MM cells. MALAT1 expression was higher in MM with t(4;14) and del 17p (p=0.049, p=0.03), but was not different among ISS (p=0.87). Higher MALAT1 expression is associated shorter progression free survival (p<0.05), and tendency of shorter overall survival (p=0.09). MM cell lines KMS12PE, OPM2, KMS11 treated with bortezomib showed elevated MALAT1 expression by 4.3 -21.8 fold and ANRIL by 2.2-4.7 fold. Cytotoxic drug doxorubicin also elevated both lnc RNAs in the cell lines. MALAT1 knockdown by GapmeR did not affect cell proliferation. The reported cell motility genes HMMR, CTHRC1 and ROD1 did not alter in MALAT1 knockdown MM cell lines, but RNA sequencing revealed the changes of many gene expressions. Finally, RNA sequencing of MM, MGUS and EMD samples revealed distinct lnc RNA expression signature as well as protein coding genes.
Conclusion
Significant upregulations of lnc RNAs MALAT1 might be associated with MM progression. Given that MALAT1 is associated with lung cancer metastasis, MALAT1 might be strongly associated with EMD formation . Genotoxic and ER stress induced by therapeutic drugs might upregulate MALAT1 leading extramedullary extension. Revealing distinct lnc RNA signature of MM is current important issue to clarify molecular mechanisms underlying MM progression and to development novel therapies.
Session topic: E-poster
Keyword(s): Epigenetic, Multiple myeloma, Progression
Abstract: E1244
Type: Eposter Presentation
Background
Recent transcriptome-wide analyses have revealed an overwhelming amount of transcribed but not translated non-coding RNAs capable of influencing diverse cellular processes such as proliferation, apoptosis, and motility. Long non-coding RNA (lnc RNAs), which are commonly defined as transcripts >200 nt in length, have emerged as a class of key regulatory RNA. LncRNAs are deregulated in diverse human cancers and associated with disease progression; however little is available in multiple myeloma (MM).
Aims
To elucidate the role of lnc RNA in MM, we studied expression pattern of several well-known lnc RNAs in plasma cells of MM, MGUS and plasmacytoma, and function in MM cell lines in vitro. Moreover, to reveal the distinct lnc RNA signature more comprehensively, we performed next generation sequencing based RNA sequencing, which is potentially able to discover novel lnc RNAs.
Methods
Purified CD138+ plasma cells from bone marrow (BM) mononuclear cells obtained from 110 of MM patients, 48 of MGUS patients, 19 of control BM and 5 of extramedullary disease (EMD) are subjected to the study after obtaining informed consent. The expression levels of lnc RNAs were determined by RQ-PCR. RNase H-activating LNA™ GapmeR antisense oligonucleotides were used to knockdown lnc RNA in vitro in MM cell lines. The cell lines were treated with bortezomib, MG132, doxorubicin to evaluate the effects of cytotoxic stress for the lnc RNA expression. RNA sequencing was performed with Illumina NextSeq 500. This study was approved by IRB of Gunma University Hospital under Declaration of Helsinki.
Results
We found significant higher level of MALAT1 expression in BM plasma cells of MM compared to MGUS and control (control vs MM, p<0.001; control vs MGUS, p=0.01; MGUS vs MM, p<0.001). MALAT1 expression in EMD was higher by 140 fold than BM MM cells. MALAT1 expression was higher in MM with t(4;14) and del 17p (p=0.049, p=0.03), but was not different among ISS (p=0.87). Higher MALAT1 expression is associated shorter progression free survival (p<0.05), and tendency of shorter overall survival (p=0.09). MM cell lines KMS12PE, OPM2, KMS11 treated with bortezomib showed elevated MALAT1 expression by 4.3 -21.8 fold and ANRIL by 2.2-4.7 fold. Cytotoxic drug doxorubicin also elevated both lnc RNAs in the cell lines. MALAT1 knockdown by GapmeR did not affect cell proliferation. The reported cell motility genes HMMR, CTHRC1 and ROD1 did not alter in MALAT1 knockdown MM cell lines, but RNA sequencing revealed the changes of many gene expressions. Finally, RNA sequencing of MM, MGUS and EMD samples revealed distinct lnc RNA expression signature as well as protein coding genes.
Conclusion
Significant upregulations of lnc RNAs MALAT1 might be associated with MM progression. Given that MALAT1 is associated with lung cancer metastasis, MALAT1 might be strongly associated with EMD formation . Genotoxic and ER stress induced by therapeutic drugs might upregulate MALAT1 leading extramedullary extension. Revealing distinct lnc RNA signature of MM is current important issue to clarify molecular mechanisms underlying MM progression and to development novel therapies.
Session topic: E-poster
Keyword(s): Epigenetic, Multiple myeloma, Progression
Type: Eposter Presentation
Background
Recent transcriptome-wide analyses have revealed an overwhelming amount of transcribed but not translated non-coding RNAs capable of influencing diverse cellular processes such as proliferation, apoptosis, and motility. Long non-coding RNA (lnc RNAs), which are commonly defined as transcripts >200 nt in length, have emerged as a class of key regulatory RNA. LncRNAs are deregulated in diverse human cancers and associated with disease progression; however little is available in multiple myeloma (MM).
Aims
To elucidate the role of lnc RNA in MM, we studied expression pattern of several well-known lnc RNAs in plasma cells of MM, MGUS and plasmacytoma, and function in MM cell lines in vitro. Moreover, to reveal the distinct lnc RNA signature more comprehensively, we performed next generation sequencing based RNA sequencing, which is potentially able to discover novel lnc RNAs.
Methods
Purified CD138+ plasma cells from bone marrow (BM) mononuclear cells obtained from 110 of MM patients, 48 of MGUS patients, 19 of control BM and 5 of extramedullary disease (EMD) are subjected to the study after obtaining informed consent. The expression levels of lnc RNAs were determined by RQ-PCR. RNase H-activating LNA™ GapmeR antisense oligonucleotides were used to knockdown lnc RNA in vitro in MM cell lines. The cell lines were treated with bortezomib, MG132, doxorubicin to evaluate the effects of cytotoxic stress for the lnc RNA expression. RNA sequencing was performed with Illumina NextSeq 500. This study was approved by IRB of Gunma University Hospital under Declaration of Helsinki.
Results
We found significant higher level of MALAT1 expression in BM plasma cells of MM compared to MGUS and control (control vs MM, p<0.001; control vs MGUS, p=0.01; MGUS vs MM, p<0.001). MALAT1 expression in EMD was higher by 140 fold than BM MM cells. MALAT1 expression was higher in MM with t(4;14) and del 17p (p=0.049, p=0.03), but was not different among ISS (p=0.87). Higher MALAT1 expression is associated shorter progression free survival (p<0.05), and tendency of shorter overall survival (p=0.09). MM cell lines KMS12PE, OPM2, KMS11 treated with bortezomib showed elevated MALAT1 expression by 4.3 -21.8 fold and ANRIL by 2.2-4.7 fold. Cytotoxic drug doxorubicin also elevated both lnc RNAs in the cell lines. MALAT1 knockdown by GapmeR did not affect cell proliferation. The reported cell motility genes HMMR, CTHRC1 and ROD1 did not alter in MALAT1 knockdown MM cell lines, but RNA sequencing revealed the changes of many gene expressions. Finally, RNA sequencing of MM, MGUS and EMD samples revealed distinct lnc RNA expression signature as well as protein coding genes.
Conclusion
Significant upregulations of lnc RNAs MALAT1 might be associated with MM progression. Given that MALAT1 is associated with lung cancer metastasis, MALAT1 might be strongly associated with EMD formation . Genotoxic and ER stress induced by therapeutic drugs might upregulate MALAT1 leading extramedullary extension. Revealing distinct lnc RNA signature of MM is current important issue to clarify molecular mechanisms underlying MM progression and to development novel therapies.
Session topic: E-poster
Keyword(s): Epigenetic, Multiple myeloma, Progression
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