Specific small nucleolar RNA expression profiles in acute leukemia

Abstract

Apart from microRNAs, little is known about the regulation of expression of non-coding RNAs in cancer. We investigated whether small nucleolar RNAs (snoRNAs) accumulation displayed specific signatures in acute myeloblastic and acute lymphoblastic leukemias. Using microarrays and high-throughput quantitative PCR (qPCR), we demonstrate here that snoRNA expression patterns are negatively altered in leukemic cells compared with controls. Interestingly, a specific signature was found in acute promyelocytic leukemia (APL) with ectopic expression of SNORD112-114 snoRNAs located at the DLK1-DIO3 locus. In vitro experiments carried out on APL blasts demonstrate 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. Further experiments revealed that the SNORD114-1 (14q(II-1)) variant promoted cell growth through cell cycle modulation; its expression was implicated in the G0/G1 to S phase transition mediated by the Rb/p16 pathways. This study thus reports three important observations: (1) snoRNA regulation is different in normal cells compared with cancer cells; (2) a relationship exists between a chromosomal translocation and expression of snoRNA loci; and (3) snoRNA expression can affect Rb/p16 cell cycle regulation. Taken together, these data strongly suggest that snoRNAs have a role in cancer development.

Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies

“…snoRNA are non-coding RNAs (ncRNA) that are less well known than other ncRNAs, such as miRNAs and siRNAs, that could be actively involved in the development of cancer. [44][45][46][47] In this setting, global downregulation is a characteristic feature of snoRNAs in cancer cells. For example, it has been recently reported that leukemic cells show infraexpression of several snoRNAs.…”

“…For example, it has been recently reported that leukemic cells show infraexpression of several snoRNAs. 47 In addition, 9 out of 126 significant differentially expressed genes in clonal PC were zinc finger proteins, which are a family of transcription factors involved in governing the response to growth factor signaling. 10,[48][49][50] CABLES1, which is a cyclindependent kinase (CDK)-binding protein that plays an inhibitor role in proliferation and/or differentiation and whose loss of expression has been found in many human cancers, 51,52 was the most under-expressed gene in clonal PC versus NPC.…”

Expression profiling of snoRNAs in normal hematopoiesis and AML

“…[12][13][14] Microarrays for snoRNAs are unable to effectively capture novel sequences or resolve the expression of snoRNAs in families with highly homologous members. 38 Standard RNA-seq is generally limited to RNA species .200 nucleotides in length, and thus does not reliably detect most sncRNAs, including snoRNAs.…”

“…11 Several groups have reported marked increased expression of snoRNAs contained in the DLK-DIO3 locus in acute promyelocytic leukemia, although their contribution to leukemogenesis is unknown. [12][13][14] The lack of a method to accurately and comprehensively assess snoRNA expression has limited research in this area. Array-based methods only interrogate a subset of snoRNAs and cannot distinguish between mature and precursor snoRNAs.…”

Array comparative genomic hybridization and sequencing of 23 genes in 80 patients with myelofibrosis at chronic or acute phase

“…SNORNAs are 60-300 nucleotide-long non-coding RNAs that are excised from intron regions of pre-mRNAs, down-regulated in leukemic cells, suggesting that they may have a role in cancer development. 44 The use of aCGH allowed the identification of abnormalities not detectable on karyotype, in particular del(17q), and del(12p) associated or not to monosomy 7. Del(17q11) was the second most recurrent CNA.…”