Integrative gene expression profiling reveals G6PD-mediated resistance to RNA-directed nucleoside analogues in B-cell neoplasms

Samuel K. McBrayer, Michael Yarrington, Jun Qian, Gang Feng, Mala Shanmugam, Varsha Gandhi, Nancy L. Krett, Steven T. Rosen

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The nucleoside analogues 8-amino-adenosine and 8-chloro-adenosine have been investigated in the context of B-lineage lymphoid malignancies by our laboratories due to the selective cytotoxicity they exhibit toward multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL) cell lines and primary cells. Encouraging pharmacokinetic and pharmacodynamic properties of 8-chloro-adenosine being documented in an ongoing Phase I trial in CLL provide additional impetus for the study of these promising drugs. In order to foster a deeper understanding of the commonalities between their mechanisms of action and gain insight into specific patient cohorts positioned to achieve maximal benefit from treatment, we devised a novel two-tiered chemoinformatic screen to identify molecular determinants of responsiveness to these compounds. This screen entailed: 1) the elucidation of gene expression patterns highly associated with the anti-tumor activity of 8-chloro-adenosine in the NCI-60 cell line panel, 2) characterization of altered transcript abundances between paired MM and MCL cell lines exhibiting differential susceptibility to 8-amino-adenosine, and 3) integration of the resulting datasets. This approach generated a signature of seven unique genes including G6PD which encodes the rate-determining enzyme of the pentose phosphate pathway (PPP), glucose-6-phosphate dehydrogenase. Bioinformatic analysis of primary cell gene expression data demonstrated that G6PD is frequently overexpressed in MM and CLL, highlighting the potential clinical implications of this finding. Utilizing the paired sensitive and resistant MM and MCL cell lines as a model system, we go on to demonstrate through loss-of-function and gain-of-function studies that elevated G6PD expression is necessary to maintain resistance to 8-amino- and 8-chloro-adenosine but insufficient to induce de novo resistance in sensitive cells. Taken together, these results indicate that G6PD activity antagonizes the cytotoxicity of 8-substituted adenosine analogues and suggests that administration of these agents to patients with B-cell malignancies exhibiting normal levels of G6PD expression may be particularly efficacious.

Original languageEnglish (US)
Article numbere41455
JournalPloS one
Volume7
Issue number7
DOIs
StatePublished - Jul 27 2012
Externally publishedYes

Fingerprint

nucleosides
glucose-6-phosphate 1-dehydrogenase
Gene Expression Profiling
adenosine
Nucleosides
Gene expression
Adenosine
B-lymphocytes
B-Lymphocytes
Cells
RNA
myeloma
gene expression
neoplasms
Multiple Myeloma
Mantle-Cell Lymphoma
lymphocytic leukemia
B-Cell Chronic Lymphocytic Leukemia
lymphoma
cell lines

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Integrative gene expression profiling reveals G6PD-mediated resistance to RNA-directed nucleoside analogues in B-cell neoplasms. / McBrayer, Samuel K.; Yarrington, Michael; Qian, Jun; Feng, Gang; Shanmugam, Mala; Gandhi, Varsha; Krett, Nancy L.; Rosen, Steven T.

In: PloS one, Vol. 7, No. 7, e41455, 27.07.2012.

Research output: Contribution to journalArticle

McBrayer, Samuel K. ; Yarrington, Michael ; Qian, Jun ; Feng, Gang ; Shanmugam, Mala ; Gandhi, Varsha ; Krett, Nancy L. ; Rosen, Steven T. / Integrative gene expression profiling reveals G6PD-mediated resistance to RNA-directed nucleoside analogues in B-cell neoplasms. In: PloS one. 2012 ; Vol. 7, No. 7.
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