MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma

Aldo M. Roccaro, Antonio Sacco, Brian Thompson, Xavier Leleu, Abdel Kareem Azab, Feda Azab, Judith Runnels, Xiaoying Jia, Hai T. Ngo, Molly R. Melhem, Charles P. Lin, Domenico Ribatti, Barrett J. Rollins, Thomas E. Witzig, Kenneth C. Anderson, Irene M. Ghobrial

Research output: Contribution to journalArticle

211 Citations (Scopus)

Abstract

Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138+ MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P <.01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-κB-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM.

Original languageEnglish
Pages (from-to)6669-6680
Number of pages12
JournalBlood
Volume113
Issue number26
DOIs
Publication statusPublished - 2009

Fingerprint

Multiple Myeloma
MicroRNAs
Tumors
Neoplasms
Bone
Bone Marrow
Ribosomal Protein S6
Ribosomal Protein S6 Kinases
Protein-Serine-Threonine Kinases
Epigenomics
Chromosome Aberrations
Phosphotransferases
Disease Progression
Polymerase Chain Reaction
Growth

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Roccaro, A. M., Sacco, A., Thompson, B., Leleu, X., Azab, A. K., Azab, F., ... Ghobrial, I. M. (2009). MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood, 113(26), 6669-6680. https://doi.org/10.1182/blood-2009-01-198408

MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. / Roccaro, Aldo M.; Sacco, Antonio; Thompson, Brian; Leleu, Xavier; Azab, Abdel Kareem; Azab, Feda; Runnels, Judith; Jia, Xiaoying; Ngo, Hai T.; Melhem, Molly R.; Lin, Charles P.; Ribatti, Domenico; Rollins, Barrett J.; Witzig, Thomas E.; Anderson, Kenneth C.; Ghobrial, Irene M.

In: Blood, Vol. 113, No. 26, 2009, p. 6669-6680.

Research output: Contribution to journalArticle

Roccaro, AM, Sacco, A, Thompson, B, Leleu, X, Azab, AK, Azab, F, Runnels, J, Jia, X, Ngo, HT, Melhem, MR, Lin, CP, Ribatti, D, Rollins, BJ, Witzig, TE, Anderson, KC & Ghobrial, IM 2009, 'MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma', Blood, vol. 113, no. 26, pp. 6669-6680. https://doi.org/10.1182/blood-2009-01-198408
Roccaro AM, Sacco A, Thompson B, Leleu X, Azab AK, Azab F et al. MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood. 2009;113(26):6669-6680. https://doi.org/10.1182/blood-2009-01-198408
Roccaro, Aldo M. ; Sacco, Antonio ; Thompson, Brian ; Leleu, Xavier ; Azab, Abdel Kareem ; Azab, Feda ; Runnels, Judith ; Jia, Xiaoying ; Ngo, Hai T. ; Melhem, Molly R. ; Lin, Charles P. ; Ribatti, Domenico ; Rollins, Barrett J. ; Witzig, Thomas E. ; Anderson, Kenneth C. ; Ghobrial, Irene M. / MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. In: Blood. 2009 ; Vol. 113, No. 26. pp. 6669-6680.
@article{f9f7e0b51c0941debcd1eecce4d3bf86,
title = "MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma",
abstract = "Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138+ MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P <.01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-κB-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM.",
author = "Roccaro, {Aldo M.} and Antonio Sacco and Brian Thompson and Xavier Leleu and Azab, {Abdel Kareem} and Feda Azab and Judith Runnels and Xiaoying Jia and Ngo, {Hai T.} and Melhem, {Molly R.} and Lin, {Charles P.} and Domenico Ribatti and Rollins, {Barrett J.} and Witzig, {Thomas E.} and Anderson, {Kenneth C.} and Ghobrial, {Irene M.}",
year = "2009",
doi = "10.1182/blood-2009-01-198408",
language = "English",
volume = "113",
pages = "6669--6680",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "26",

}

TY - JOUR

T1 - MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma

AU - Roccaro, Aldo M.

AU - Sacco, Antonio

AU - Thompson, Brian

AU - Leleu, Xavier

AU - Azab, Abdel Kareem

AU - Azab, Feda

AU - Runnels, Judith

AU - Jia, Xiaoying

AU - Ngo, Hai T.

AU - Melhem, Molly R.

AU - Lin, Charles P.

AU - Ribatti, Domenico

AU - Rollins, Barrett J.

AU - Witzig, Thomas E.

AU - Anderson, Kenneth C.

AU - Ghobrial, Irene M.

PY - 2009

Y1 - 2009

N2 - Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138+ MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P <.01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-κB-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM.

AB - Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138+ MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P <.01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-κB-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM.

UR - http://www.scopus.com/inward/record.url?scp=69249225706&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69249225706&partnerID=8YFLogxK

U2 - 10.1182/blood-2009-01-198408

DO - 10.1182/blood-2009-01-198408

M3 - Article

VL - 113

SP - 6669

EP - 6680

JO - Blood

JF - Blood

SN - 0006-4971

IS - 26

ER -