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Identification of GPM6A and GPM6B as potential new human lymphoid leukemia-associated oncogenes

Cellular Oncology volume 37, pages 179–191 (2014)Cite this article

Abstract

Background

Previously, we found that the Graffi murine leukemia virus (MuLV) is able to induce a wide spectrum of hematologic malignancies in vivo. Using high-density oligonucleotide microarrays, we established the gene expression profiles of several of these malignancies, thereby specifically focusing on genes deregulated in the lymphoid sub-types. We observed over-expression of a variety of genes, including Arntl2, Bfsp2, Gfra2, Gpm6a, Gpm6b, Nln, Fbln1, Bmp7, Etv5 and Celsr1 and, in addition, provided evidence that Fmn2 and Parm-1 may act as novel oncogenes. In the present study, we assessed the expression patterns of eight selected human homologs of these genes in primary human B-cell malignancies, and explored the putative oncogenic potential of GPM6A and GPM6B.

Methods

The gene expression levels of the selected human homologs were tested in human B-cell malignancies by semi-quantitative RT-PCR. The protein expression profiles of human GPM6A and GPM6B were analyzed by Western blotting. The localization and the effect of GPM6A and GPM6B on the cytoskeleton were determined using confocal and indirect immunofluorescence microscopy. To confirm the oncogenic potential of GPM6A and GPM6B, classical colony formation assays in soft agar and focus forming assays were used. The effects of these proteins on the cell cycle were assessed by flow cytometry analysis.

Results

Using semi-quantitative RT-PCR, we found that most of the primary B-cell malignancies assessed showed altered expression patterns of the genes tested, including GPM6A and GPM6B. Using confocal microscopy, we found that the GPM6A protein (isoform 3) exhibits a punctate cytoplasmic localization and that the GPM6B protein (isoform 4) exhibits a peri-nuclear and punctate cytoplasmic localization. Interestingly, we found that exogenous over-expression of both proteins in NIH/3T3 cells alters the actin and microtubule networks and induces the formation of long filopodia-like protrusions. Additionally, we found that these over-expressing NIH/3T3 cells exhibit anchorage-independent growth and enhanced proliferation rates. Cellular transformation (i.e., loss of contact inhibition) was, however, only observed after exogenous over-expression of GPM6B.

Conclusions

Our results indicate that several human homologs of the genes found to be deregulated in Graffi MuLV experimental mouse models may serve as candidate biomarkers for human B-cell malignancies. In addition, we found that GPM6A and GPM6B may act as novel oncogenes in the development of these malignancies.

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Acknowledgments

We thank Dr. Daniel Sinnet for providing the pediatric tumor samples, Bertrand Fournier for his help with the statistical analysis and Denis Flipo for his help with the confocal microscopy analyses. This work was supported by the Canadian Institutes of Health Research, grant MOP-37994 (ER). CC is a recipient of a studentship from the Tunisia Government and Fondation UQAM.

Conflict of interest

The authors declare that they have no competing interests.

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  1. Laboratoire de Biologie Moléculaire, Département des Sciences Biologiques, Centre BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C-3P8, Canada

    Cyndia Charfi, Elsy Edouard & Eric Rassart

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  1. Cyndia Charfi
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  2. Elsy Edouard
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  3. Eric Rassart
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Correspondence to Elsy Edouard or Eric Rassart.

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Online Resource Fig. 1

Alignment of deduced amino acid sequences for GPM6A isoforms together and for GPM6B isoforms together. Alignment a of the 5 Homo sapiens isoforms of GPM6A (NP_005268 (isoform 1), NP_963885 (isoform 1), NP_001248376 (isoform 2), NP_963886 (isoform 3) and NP_001248377 (isoform 4)) and b of the 4 homosapiens isoforms of GPM6B protein (NP_001001995 (isoform 1), NP_005269 (isoform 3), NP_001001996 (isoform 2) and NP_001001994 (isoform 4)) using the Clustal Omega software. Stars indicate a perfect match between all aligned isoforms and dashed lines indicate gaps. (PDF 30 kb)

Online Resource Fig. 2

Alignment of GPM6A, GPM6B and DM20 proteins. The amino acid residues of GPM6A isoform 3, GPM6B isoform 4 and DM20 proteins were aligned in pairs to determine their identity percentage. a Alignment of GPM6A isoform 3 and GPM6B isoform 4. b Alignment of DM20 and GPM6A isoform 3. c Alignment of DM20 and GPM6B isoform 4. Boxes: N- and C- cytoplasmic tails, dotted lines: transmembrane domains, lines: extracellular loops, double lines: intracellular loop. (PDF 48 kb)

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Charfi, C., Edouard, E. & Rassart, E. Identification of GPM6A and GPM6B as potential new human lymphoid leukemia-associated oncogenes. Cell Oncol. 37, 179–191 (2014). https://doi.org/10.1007/s13402-014-0171-y

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Keywords

  • B-cell leukemia
  • Gene expression profiling
  • Graffi MuLV
  • GPM6A
  • GPM6B
  • Oncogenes