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Blood Cancer J. 2012 October; 2(10): e92.
Published online 2012 October 12. doi:  10.1038/bcj.2012.39
PMCID: PMC3483620

The increased expression of 14q32 small nucleolar RNA transcripts in promyelocytic leukemia cells is not dependent on PML–RARA fusion gene

On May 2012 issue of Leukemia, Valleron et al.1 presented a specific gene-expression signature, characterizing acute promyelocytic leukemia (APL), which was recognizable by ectopic expression of SNORD112–114 small nucleolar RNAs (snoRNAs) located at the DLK1-DIO3 locus. These findings were obtained using microarrays and a high-throughput quantitative PCR strategy. In their in vitro experiments carried out on APL blasts, Valleron et al. noticed that transcription of these snoRNAs was lost under all-trans retinoic acid-mediated differentiation and induced by enforced expression of the PML–RARalpha fusion protein in negative leukemic cell lines. Although PML–RARalpha seemed to be implicated in DLK1-DIO3 snoRNA expression, no direct relationship could be demonstrated, but a binding site for PML–RARalpha was reported close to the DLK1 gene using chip sequencing.2 Further experiments revealed that the SNORD114-1 (14q(II-1)) variant promoted cell growth through cell-cycle modulation. In addition, transcription of 14q32 snoRNAs was induced by enforced expression of PML–RARalpha fusion protein in negative leukemic cell lines.1

Recently, we recorded global gene-expression profile (GEP) changes in bone marrow (BM) samples from patients with various hematological malignancies along several time points following BM aspiration.3 By comparing the various GEPs obtained, a clear difference was seen between the three APL cases to all other cases in expression of various transcripts (Figure 1). The maximal differences were seen in SNORD113-3 SNORD113-4, SNORD114-2 and SNORD114-3, for which the expression was many folds higher in the BM samples from the 3 APL cases compared with the samples from 2 cases with other acute myeloid leukemia (AML) subtypes, 10 cases with multiple myeloma (MM), a case with MM in remission and a case with large B-cell lymphoma infiltrating the BM. The APL-related gene signature also involved several other overexpressed genes mainly in 14q32 region, which included MIR154 (14q32.31) and MIR382 (14q32.31) being consistent with Valleron et al results. However, the most important point relating to the findings of Valleron et al. was that in one of our three APL cases (case 15), the translocation was not between PML and RARA but between RARA and yet unknown partner gene in a t(3:17)(q26;q21) translocation (Figure 2). At the presentation, this patient had hyperleukocytosis and the BM karyotype included X0 in addition to the t(3:17) translocation, but the cell morphology and immunophenotype were typical for APL. Our conclusion is that the increased expression of the various 14q32 transcripts in APL, which was attributed to PML–RARA fusion gene, is not dependent exclusively on PML fusion with RARA. It is reasonable then that RARalpha is the critical partner in this context. Interestingly, the influence of chromosomal translocations on expression of snoRNAs was also demonstrated recently in MM, where ACA11 (SCARNA22), an orphan snoRNA encoded in an intron of the WHSC1(FGFR3) gene, was found to be aberrantly overexpressed in t(4;14)-positive MM cells.4, 5

Figure 1
(a, b) Expression of snoRNAs in APL vs other BM tumor cells. BM samples from patients with APL, AML, MM, MM in complete remission (CR) and large B-cell lymphoma (L) infiltrating the BM were analyzed by microarray at different time points following aspiration. ...
Figure 2
(A, B) Karyotype and fluorescence in situ hybridization (FISH) images from an APL case with t(3:17). The karyotype was consistent with 45 X, t(3;17)(q26;q21). FISH analysis revealed: a, RARA rearrangement detected by LSI RARA Break Apart probe and b, ...

Notes

The authors declare no conflict of interest.

References

  • Valleron W, Laprevotte E, Gautier EF, Quelen C, Demur C, Delabesse E, et al. Specific small nucleolar RNA expression profiles in acute leukemia. Leukemia. 2012;26:2052–2060. [PubMed]
  • Martens JH, Brinkman AB, Simmer F, Francoijs KJ, Nebbioso A, Ferrara F, et al. PML-RARalpha/RXR alters the epigenetic landscape in acute promyelocytic leukemia. Cancer Cell. 2010;17:173–185. [PubMed]
  • Cohen Y, Garach-Jehoshua O, Bar-Chaim A, Kornberg A. Niche modulated and niche modulating genes in multiple myeloma Blood Cancer J 2012(in publication). [PMC free article] [PubMed]
  • Chu L, Su MY, Maggi LB, Lu L, Mullins C, Crosby S, et al. Multiple myeloma-associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress. J Clin Invest. 2012;pii:63051. [PMC free article] [PubMed]
  • Taulli R, Pandolfi PP. “Snorkeling” for missing players in cancer. J Clin Invest. 2012;2:1–4. [PMC free article] [PubMed]

Articles from Blood Cancer Journal are provided here courtesy of Nature Publishing Group