Overexpression of SNORD 1143 marks acute promyelocytic leukemia

A global downregulation of small nucleolar RNAs (snoRNA) was reported in acute lymphoblastic (ALL) and acute myeloid leukemias (AML) by Valleron et al. The authors also identified a specific snoRNA signature in acute promyelocytic leukemia (APL) with overexpression of snoRNA clusters SNORD112-114. Recently, Cohen et al. reported a marked overexpression of SNORD113-3, SNORD113-4, SNORD114-2 and SNORD114-3 in three additional cases of APL. We have compiled a hematological gene expression data set of neoplastic and non-neoplastic samples hybridized to Affymetrix HGU133 Plus 2.0 GeneChips, all downloaded from the GEO microarray repository. The data were collected as described earlier by Heinäniemi et al. Of all the genes on the microarray, 15 were identified as snoRNAs (Table 1). They represent various types of snoRNAs, including H/ACA and CD box types, small Cajal body-specific RNAs (scaRNA), intergenic and intronic snoRNAs, and even one snoRNA without any known target RNA (so-called ‘orphan’ snoRNA). To study the expression of the 15 snoRNAs, we focused on 883 cases of pediatric leukemias, which were subdivided into three classes: early B-ALL, T-ALL and AML. In addition, we considered 35 non-neoplastic samples consisting of hematopoietic stem cells (HSCs) along with naive Band naive T-lymphocytes. In most cases, the snoRNAs were expressed in a relatively uniform manner across all leukemia subtypes and normal blood cells (Figure 1a). In our limited set of 15 snoRNAs, we did not observe a lower expression in acute leukemias as compared with HSCs and naive lymphocytes. Two snoRNAs, SNORA70 and SNORD104, were expressed consistently higher than other snoRNAs in leukemic as well as healthy samples. They were expressed at a level approximately fourfold higher relative to other snoRNAs (Figure 1a). Interestingly, SNORA25 and SNORA61 were expressed strongly in naive, or unstimulated, B cells compared to HSCs, naive T cells and leukemias, suggesting B-cell differentiation-dependent regulation of expression (Figure 1a). At single patient level, the expression of individual snoRNAs remained again rather constant except for SNORD114-3 (Figure 1a and Supplementary Figure S1). Among the 237 pediatric AML patients, 15 were found to have increased expression of SNORD114-3 when the cut-off level in log2-expression was set at 7 (Figure 1b). Interestingly, 13 out of these 15 patients harbored t(15;17) translocation, the hallmark of APL. In the two remaining t(15;17)-negative patients, the expression was only slightly above the threshold level of 7. These two samples did not fall into any major cytogenetic subtype of AML, but one of them had an internal tandem duplication of FLT3 and the other carried a mutation in either NRAS or KRAS. Among the cases with normal SNORD114-3 expression, only six patients out of 222, or 2.7%, were identified as t(15;17)-positive patients. Four of these six APL cases were carrying FLT3-ITD. A similar pattern emerged also in the cohort of 1117 adult AML patients in our database, 69 of which were of promyelocytic subtype (Figure 1c). One-hundred and nine adult AML samples were found with an elevated SNORD114-3 expression (keeping the threshold at 7). Out of them, 50 were from APL patients. From the adult samples with normal SNORD114-3 expression, only 19, or 1.9%, were classified as APL. The expression level of SNORD114-3 differentiated the APL-positive and -negative cases among both pediatric (Po10 ) and adult AML (Po10 ). Mann–Whitney U-test was used to assess statistical significance.